Neuroinflammation in Alzheimer's Disease

. 2021 May 07 ; 9 (5) : . [epub] 20210507

Status PubMed-not-MEDLINE Jazyk angličtina Země Švýcarsko Médium electronic

Typ dokumentu časopisecké články, přehledy

Perzistentní odkaz   https://www.medvik.cz/link/pmid34067173

Grantová podpora
CZ.02.1.01/0.0/0.0/16_019/0000868 European Regional Development Fund- Project ENOCH 750

Odkazy

PubMed 34067173
PubMed Central PMC8150909
DOI 10.3390/biomedicines9050524
PII: biomedicines9050524
Knihovny.cz E-zdroje

Alzheimer's disease (AD) is a neurodegenerative disease associated with human aging. Ten percent of individuals over 65 years have AD and its prevalence continues to rise with increasing age. There are currently no effective disease modifying treatments for AD, resulting in increasingly large socioeconomic and personal costs. Increasing age is associated with an increase in low-grade chronic inflammation (inflammaging) that may contribute to the neurodegenerative process in AD. Although the exact mechanisms remain unclear, aberrant elevation of reactive oxygen and nitrogen species (RONS) levels from several endogenous and exogenous processes in the brain may not only affect cell signaling, but also trigger cellular senescence, inflammation, and pyroptosis. Moreover, a compromised immune privilege of the brain that allows the infiltration of peripheral immune cells and infectious agents may play a role. Additionally, meta-inflammation as well as gut microbiota dysbiosis may drive the neuroinflammatory process. Considering that inflammatory/immune pathways are dysregulated in parallel with cognitive dysfunction in AD, elucidating the relationship between the central nervous system and the immune system may facilitate the development of a safe and effective therapy for AD. We discuss some current ideas on processes in inflammaging that appear to drive the neurodegenerative process in AD and summarize details on a few immunomodulatory strategies being developed to selectively target the detrimental aspects of neuroinflammation without affecting defense mechanisms against pathogens and tissue damage.

Zobrazit více v PubMed

Pattabiraman G., Palasiewicz K., Galvin J.P., Ucker D.S. Aging-associated dysregulation of homeostatic immune response termination (and not initiation) Aging Cell. 2017;16:585–593. doi: 10.1111/acel.12589. PubMed DOI PMC

López-Otín C., Blasco M.A., Partridge L., Serrano M., Kroemer G. The Hallmarks of Aging. Cell. 2013;153:1194–1217. doi: 10.1016/j.cell.2013.05.039. PubMed DOI PMC

Spinelli R., Parrillo L., Longo M., Florese P., Desiderio A., Zatterale F., Miele C., Raciti G.A., Beguinot F. Molecular basis of ageing in chronic metabolic diseases. J. Endocrinol. Investig. 2020;43:1373–1389. doi: 10.1007/s40618-020-01255-z. PubMed DOI PMC

Franceschi C., Bonafè M., Valensin S., Olivieri F., De Luca M., Ottaviani E., De Benedictis G. Inflamm-aging: An evolutionary perspective on immunosenescence. Ann. N. Y. Acad. Sci. 2000;908:244–254. doi: 10.1111/j.1749-6632.2000.tb06651.x. PubMed DOI

Li T., Huang Y., Cai W., Chen X., Men X., Lu T., Wu A., Lu Z. Age-related cerebral small vessel disease and inflammaging. Cell Death Dis. 2020;11:1–12. doi: 10.1038/s41419-020-03137-x. PubMed DOI PMC

Di Micco R., Krizhanovsky V., Baker D., d’Adda di Fagagna F. Cellular senescence in ageing: From mechanisms to therapeutic opportunities. Nat. Rev. Mol. Cell Biol. 2021;22:75–95. doi: 10.1038/s41580-020-00314-w. PubMed DOI PMC

Fulop T., Larbi A., Dupuis G., Le Page A., Frost E.H., Cohen A.A., Witkowski J.M., Franceschi C. Immunosenescence and Inflamm-Aging As Two Sides of the Same Coin: Friends or Foes? Front. Immunol. 2018;8:1960. doi: 10.3389/fimmu.2017.01960. PubMed DOI PMC

Franceschi C., Santoro A., Capri M. The complex relationship between Immunosenescence and Inflammaging: Special issue on the New Biomedical Perspectives. Semin. Immunopathol. 2020;42:517–520. doi: 10.1007/s00281-020-00823-y. PubMed DOI PMC

Aiello A., Farzaneh F., Candore G., Caruso C., Davinelli S., Gambino C.M., Ligotti M.E., Zareian N., Accardi G. Immunosenescence and Its Hallmarks: How to Oppose Aging Strategically? A Review of Potential Options for Therapeutic Intervention. Front. Immunol. 2019;10:2247. doi: 10.3389/fimmu.2019.02247. PubMed DOI PMC

Barbé-Tuana F., Funchal G., Schmitz C.R.R., Maurmann R.M., Bauer M.E. The interplay between immunosenescence and age-related diseases. Semin. Immunopathol. 2020;42:545–557. doi: 10.1007/s00281-020-00806-z. PubMed DOI PMC

Conte M., Martucci M., Chiariello A., Franceschi C., Salvioli S. Mitochondria, immunosenescence and inflammaging: A role for mitokines? Semin. Immunopathol. 2020;42:607–617. doi: 10.1007/s00281-020-00813-0. PubMed DOI PMC

Haas R.H. Mitochondrial Dysfunction in Aging and Diseases of Aging. Biology. 2019;8:48. doi: 10.3390/biology8020048. PubMed DOI PMC

Salminen A., Kaarniranta K., Kauppinen A. Inflammaging: Disturbed interplay between autophagy and inflammasomes. Aging. 2012;4:166–175. doi: 10.18632/aging.100444. PubMed DOI PMC

Barbosa M.C., Grosso R.A., Fader C.M. Hallmarks of Aging: An Autophagic Perspective. Front. Endocrinol. 2019;9:790. doi: 10.3389/fendo.2018.00790. PubMed DOI PMC

Picca A., Lezza A.M.S., Leeuwenburgh C., Pesce V., Calvani R., Landi F., Bernabei R., Marzetti E. Fueling Inflamm-Aging through Mitochondrial Dysfunction: Mechanisms and Molecular Targets. Int. J. Mol. Sci. 2017;18:933. doi: 10.3390/ijms18050933. PubMed DOI PMC

Tran M., Reddy P.H. Defective Autophagy and Mitophagy in Aging and Alzheimer’s Disease. Front. Neurosci. 2021;14 doi: 10.3389/fnins.2020.612757. PubMed DOI PMC

Lopez-Castejon G. Control of the inflammasome by the ubiquitin system. FEBS J. 2020;287:11–26. doi: 10.1111/febs.15118. PubMed DOI PMC

Hegde A.N., Smith S.G., Duke L.M., Pourquoi A., Vaz S. Perturbations of Ubiquitin-Proteasome-Mediated Proteolysis in Aging and Alzheimer’s Disease. Front. Aging Neurosci. 2019;11:324. doi: 10.3389/fnagi.2019.00324. PubMed DOI PMC

Ioannidou A., Goulielmaki E., Garinis G.A. DNA Damage: From Chronic Inflammation to Age-Related Deterioration. Front. Genet. 2016;7:187. doi: 10.3389/fgene.2016.00187. PubMed DOI PMC

da Silva P.F.L., Schumacher B. DNA damage responses in ageing. Open Biol. 2019;9:190168. doi: 10.1098/rsob.190168. PubMed DOI PMC

Chen G., Yung R. Meta-inflammaging at the crossroad of geroscience. Aging Med. 2019;2:157–161. doi: 10.1002/agm2.12078. PubMed DOI PMC

Herradon G., Ramos-Alvarez M.P., Gramage E. Connecting Metainflammation and Neuroinflammation Through the PTN-MK-RPTPβ/ζ Axis: Relevance in Therapeutic Development. Front. Pharmacol. 2019;10:10. doi: 10.3389/fphar.2019.00377. PubMed DOI PMC

Vitale G., Salvioli S., Franceschi C. Oxidative stress and the ageing endocrine system. Nat. Rev. Endocrinol. 2013;9:228–240. doi: 10.1038/nrendo.2013.29. PubMed DOI

Shintouo C.M., Mets T., Beckwee D., Bautmans I., Ghogomu S.M., Souopgui J., Leemans L., Meriki H.D., Njemini R. Is inflammageing influenced by the microbiota in the aged gut? A systematic review. Exp. Gerontol. 2020;141:111079. doi: 10.1016/j.exger.2020.111079. PubMed DOI

Santoro A., Zhao J., Wu L., Carru C., Biagi E., Franceschi C. Microbiomes other than the gut: Inflammaging and age-related diseases. Semin. Immunopathol. 2020;42:589–605. doi: 10.1007/s00281-020-00814-z. PubMed DOI PMC

Tang Y., Fung E., Xu A., Lan H.-Y. C-reactive protein and ageing. Clin. Exp. Pharmacol. Physiol. 2017;44:9–14. doi: 10.1111/1440-1681.12758. PubMed DOI

Rea I.M., Gibson D.S., McGilligan V., McNerlan S.E., Alexander H.D., Ross O.A. Age and Age-Related Diseases: Role of Inflammation Triggers and Cytokines. Front. Immunol. 2018;9:586. doi: 10.3389/fimmu.2018.00586. PubMed DOI PMC

Marcos-Pérez D., Sánchez-Flores M., Proietti S., Bonassi S., Costa S., Teixeira J.P., Fernández-Tajes J., Pásaro E., Laffon B., Valdiglesias V. Association of inflammatory mediators with frailty status in older adults: Results from a systematic review and meta-analysis. GeroScience. 2020;42:1451–1473. doi: 10.1007/s11357-020-00247-4. PubMed DOI PMC

Tchalla A.E., Wellenius G.A., Travison T.G., Gagnon M., Iloputaife I., Dantoine T., Sorond F.A., Lipsitz L.A. Circulating Vascular Cell Adhesion Molecule-1 Is Associated With Cerebral Blood Flow Dysregulation, Mobility Impairment, and Falls in Older Adults. Hypertension. 2015;66:340–346. doi: 10.1161/HYPERTENSIONAHA.115.05180. PubMed DOI PMC

Prochaska J.H., Frank B., Nagler M., Lamparter H., Weißer G., Schulz A., Eggebrecht L., Göbel S., Arnold N., Panova-Noeva M., et al. Age-related diagnostic value of D-dimer testing and the role of inflammation in patients with suspected deep vein thrombosis. Sci. Rep. 2017;7:1–10. doi: 10.1038/s41598-017-04843-x. PubMed DOI PMC

Lee S.-H., Lee J.-H., Lee H.-Y., Min A.K.-J. Sirtuin signaling in cellular senescence and aging. BMB Rep. 2019;52:24–34. doi: 10.5483/BMBRep.2019.52.1.290. PubMed DOI PMC

Franceschi C., Campisi J. Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. J. Gerontol. A Biol. Sci. Med. Sci. 2014;69:4–9. doi: 10.1093/gerona/glu057. PubMed DOI

Kennedy B.K., Berger S.L., Brunet A., Campisi J., Cuervo A.M., Epel E.S., Franceschi C., Lithgow G.J., Morimoto R.I., Pessin J.E., et al. Geroscience: Linking Aging to Chronic Disease. Cell. 2014;159:709–713. doi: 10.1016/j.cell.2014.10.039. PubMed DOI PMC

Chen W.-W., Zhang X., Huang W.-J. Role of neuroinflammation in neurodegenerative diseases (Review) Mol. Med. Rep. 2016;13:3391–3396. doi: 10.3892/mmr.2016.4948. PubMed DOI PMC

Gross A.L., Walker K.A., Moghekar A.R., Pettigrew C., Soldan A., Albert M.S., Walston J.D. Plasma Markers of Inflammation Linked to Clinical Progression and Decline During Preclinical AD. Front. Aging Neurosci. 2019;11:229. doi: 10.3389/fnagi.2019.00229. PubMed DOI PMC

Kuo C.-Y., Stachiv I., Nikolai T. Association of Late Life Depression, (Non-) Modifiable Risk and Protective Factors with Dementia and Alzheimer’s Disease: Literature Review on Current Evidences, Preventive Interventions and Possible Future Trends in Prevention and Treatment of Dementia. Int. J. Environ. Res. Public Health. 2020;17:7475. doi: 10.3390/ijerph17207475. PubMed DOI PMC

Hou Y., Dan X., Babbar M., Wei Y., Hasselbalch S.G., Croteau D.L., Bohr V.A. Ageing as a risk factor for neurodegenerative disease. Nat. Rev. Neurol. 2019;15:565–581. doi: 10.1038/s41582-019-0244-7. PubMed DOI

Cummings J. New approaches to symptomatic treatments for Alzheimer’s disease. Mol. Neurodegener. 2021;16:1–13. doi: 10.1186/s13024-021-00424-9. PubMed DOI PMC

Yiannopoulou K.G., Papageorgiou S.G. Current and future treatments for Alzheimer’s disease. Ther. Adv. Neurol. Disord. 2013;6:19–33. doi: 10.1177/1756285612461679. PubMed DOI PMC

Deture M.A., Dickson D.W. The neuropathological diagnosis of Alzheimer’s disease. Mol. Neurodegener. 2019;14:32. doi: 10.1186/s13024-019-0333-5. PubMed DOI PMC

Masters C.L., Bateman R., Blennow K., Rowe C.C., Sperling R.A., Cummings J.L. Alzheimer’s disease. Nat. Rev. Dis. Primers. 2015;1:15056. doi: 10.1038/nrdp.2015.56. PubMed DOI

Roda A.R., Montoliu-Gaya L., Serra-Mir G., Villegas S. Both Amyloid-β Peptide and Tau Protein Are Affected by an Anti-Amyloid-β Antibody Fragment in Elderly 3xTg-AD Mice. Int. J. Mol. Sci. 2020;21:6630. doi: 10.3390/ijms21186630. PubMed DOI PMC

Reitz C., Rogaeva E., Beecham G.W. Late-onset vs nonmendelian early-onset Alzheimer disease: A distinction without a difference? Neurol. Genet. 2020;6:e512. doi: 10.1212/NXG.0000000000000512. PubMed DOI PMC

Reitz C., Mayeux R. Alzheimer disease: Epidemiology, diagnostic criteria, risk factors and biomarkers. Biochem. Pharmacol. 2014;88:640–651. doi: 10.1016/j.bcp.2013.12.024. PubMed DOI PMC

Cruchaga C., Del-Aguila J.L., Saef B., Black K., Fernandez M.V., Budde J., Ibanez L., Deming Y., Kapoor M., Tosto G., et al. Polygenic risk score of sporadic late-onset Alzheimer’s disease reveals a shared architecture with the familial and early-onset forms. Alzheimer’s Dement. 2018;14:205–214. doi: 10.1016/j.jalz.2017.08.013. PubMed DOI PMC

Kelleher R.J., 3rd, Shen J. Presenilin-1 mutations and Alzheimer’s disease. Proc. Natl. Acad. Sci. USA. 2017;114:629–631. doi: 10.1073/pnas.1619574114. PubMed DOI PMC

A An S.S., Cai Y., Kim S. Mutations in presenilin 2 and its implications in Alzheimer’s disease and other dementia-associated disorders. Clin. Interv. Aging. 2015;10:1163–1172. doi: 10.2147/CIA.S85808. PubMed DOI PMC

Tambini M.D., A Norris K., D’Adamio L. Opposite changes in APP processing and human Aβ levels in rats carrying either a protective or a pathogenic APP mutation. eLife. 2020;9:9. doi: 10.7554/eLife.52612. PubMed DOI PMC

Vidal C., Zhang L. An Analysis of the Neurological and Molecular Alterations Underlying the Pathogenesis of Alzheimer’s Disease. Cells. 2021;10:546. doi: 10.3390/cells10030546. PubMed DOI PMC

Tang M., Ryman D.C., McDade E., Jasielec M.S., Buckles V.D., Cairns N.J., Faga A.M., Goate A., Marcus D.S., Xiong C., et al. Neurological manifestations of autosomal dominant familial Alzheimer’s disease: A comparison of the published literature with the dominantly inherited Alzheimer network observational study (DIAN-OBS) Lancet Neurol. 2016;15:1317–1325. doi: 10.1016/S1474-4422(16)30229-0. PubMed DOI PMC

Guerreiro R., Bras J. The age factor in Alzheimer’s disease. Genome Med. 2015;7:106. doi: 10.1186/s13073-015-0232-5. PubMed DOI PMC

Corder E.H., Saunders A.M., Strittmatter W.J., Schmechel D.E., Gaskell P.C., Small G.W., Roses A.D., Haines J.L., Pericak-Vance M.A. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science. 1993;261:921–923. doi: 10.1126/science.8346443. PubMed DOI

Naj A.C., Schellenberg G.D. Alzheimer’s Disease Genetics Consortium (ADGC). Genomic variants, genes, and pathways of Alzheimer’s disease: An overview. Am. J. Med. Genet. B Neuropsychiatr. Genet. 2017;174:5–26. doi: 10.1002/ajmg.b.32499. PubMed DOI PMC

Prokopenko D., Morgan S.L., Mullin K., Hofmann O., Chapman B., Kirchner R., Amberkar S., Wohlers I., Lange C., Hide W., et al. Whole-genome sequencing reveals new Alzheimer’s disease–associated rare variants in loci related to synaptic function and neuronal development. Alzheimer’s Dement. 2021 doi: 10.1002/alz.12319. PubMed DOI PMC

Karch C.M., Goate A.M. Alzheimer’s disease risk genes and mechanisms of disease pathogenesis. Biol. Psychiatry. 2015;77:43–51. doi: 10.1016/j.biopsych.2014.05.006. PubMed DOI PMC

Grozeva D., Saad S., Menzies G.E., Sims R. Benefits and Challenges of Rare Genetic Variation in Alzheimer’s Disease. Curr. Genet. Med. Rep. 2019;7:53–62. doi: 10.1007/s40142-019-0161-5. DOI

Lord J., Lu A.J., Cruchaga C. Identification of rare variants in Alzheimer’s disease. Front. Genet. 2014;5:369. doi: 10.3389/fgene.2014.00369. PubMed DOI PMC

Lambert J.C., Ibrahim-Verbaas C.A., Harold D., Naj A.C., Sims R., Bellenguez C., DeStafano A.L., Bis J.C., Beecham G.W., Grenier-Boley B., et al. Meta-Analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease. Nat. Genet. 2013;45:1452–1458. doi: 10.1038/ng.2802. PubMed DOI PMC

Sims R., van der Lee S.J., Naj A.C., Bellenguez C., Badarinarayan N., Jakobsdottir J., Kunkle B.W., Boland A., Raybould R., Bis J.C., et al. Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer’s disease. Nat. Genet. 2017;49:1373–1384. doi: 10.1038/ng.3916. PubMed DOI PMC

Efthymiou A.G., Goate A.M. Late onset Alzheimer’s disease genetics implicates microglial pathways in disease risk. Mol. Neurodegener. 2017;12 doi: 10.1186/s13024-017-0184-x. PubMed DOI PMC

Gratuze M., Leyns C.E.G., Holtzman D.M. New insights into the role of TREM2 in Alzheimer’s disease. Mol. Neurodegener. 2018;13:1–16. doi: 10.1186/s13024-018-0298-9. PubMed DOI PMC

Shi Y., Holtzman D.M. Interplay between innate immunity and Alzheimer disease: APOE and TREM2 in the spotlight. Nat. Rev. Immunol. 2018;18:759–772. doi: 10.1038/s41577-018-0051-1. PubMed DOI PMC

Klein H.-U., McCabe C., Gjoneska E., Sullivan S.E., Kaskow B.J., Tang A., Smith R.V., Xu J., Pfenning A.R., Bernstein B.E., et al. Epigenome-wide study uncovers large-scale changes in histone acetylation driven by tau pathology in aging and Alzheimer’s human brains. Nat. Neurosci. 2019;22:37–46. doi: 10.1038/s41593-018-0291-1. PubMed DOI PMC

Lin Y.T., Seo J., Gao F., Feldman H.M., Wen H.L., Penney J., Cam H.P., Gjoneska E., Raja W.K., Cheng J., et al. APOE4 causes widespread molecular and cellular alterations associated with Alzheimer’s disease phenotypes in human iPSC-derived brain cell types. Neuron. 2018;98:1141–1154. doi: 10.1016/j.neuron.2018.05.008. PubMed DOI PMC

Gambhir I., Misra A., Chakrabarti S. New genetic players in late-onset Alzheimer’s disease: Findings of genome-wide association studies. Indian J. Med Res. 2018;148:135–144. doi: 10.4103/ijmr.IJMR_473_17. PubMed DOI PMC

Selkoe D.J., Hardy J. The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Mol. Med. 2016;8:595–608. doi: 10.15252/emmm.201606210. PubMed DOI PMC

Guerreiro R., Wojtas A., Bras J., Carrasquillo M.M., Rogaeva E., Majounie E., Cruchaga C., Sassi C., Kauwe J.S., Younkin S.G., et al. TREM2 Variants in Alzheimer’s Disease. N. Engl. J. Med. 2013;368:117–127. doi: 10.1056/NEJMoa1211851. PubMed DOI PMC

Li J.-T., Zhang Y. TREM2 regulates innate immunity in Alzheimer’s disease. J. Neuroinflamm. 2018;15 doi: 10.1186/s12974-018-1148-y. PubMed DOI PMC

Zheng H., Cheng B., Li Y., Li X., Chen X., Zhang Y.-W. TREM2 in Alzheimer’s Disease: Microglial Survival and Energy Metabolism. Front. Aging Neurosci. 2018;10:395. doi: 10.3389/fnagi.2018.00395. PubMed DOI PMC

Zhong L., Chen X.-F., Wang T., Wang Z., Liao C., Wang Z., Huang R., Wang D., Li X., Wu L., et al. Soluble TREM2 induces inflammatory responses and enhances microglial survival. J. Exp. Med. 2017;214:597–607. doi: 10.1084/jem.20160844. PubMed DOI PMC

Hickman S.E., El Khoury J. TREM2 and the neuroimmunology of Alzheimer’s disease. Biochem. Pharmacol. 2014;88:495–498. doi: 10.1016/j.bcp.2013.11.021. PubMed DOI PMC

Gong C.-X., Liu F., Iqbal K. Multifactorial Hypothesis and Multi-Targets for Alzheimer’s Disease. J. Alzheimer’s Dis. 2018;64:S107–S117. doi: 10.3233/JAD-179921. PubMed DOI

De Roeck A., Van Broeckhoven C., Sleegers K. The role of ABCA7 in Alzheimer’s disease: Evidence from genomics, transcriptomics and methylomics. Acta Neuropathol. 2019;138:201–220. doi: 10.1007/s00401-019-01994-1. PubMed DOI PMC

Iqbal K., Grundke-Iqbal I. Alzheimer’s disease, a multifactorial disorder seeking multitherapies. Alzheimer's Dement. 2010;6:420–424. doi: 10.1016/j.jalz.2010.04.006. PubMed DOI PMC

Heppner F.L., Ransohoff R.M., Becher B. Immune attack: The role of inflammation in Alzheimer disease. Nat. Rev. Neurosci. 2015;16:358–372. doi: 10.1038/nrn3880. PubMed DOI

Sala Frigerio C., Wolfs L., Fattorelli N., Thrupp N., Voytyuk I., Schmidt I., Mancuso R., Chen W.T., Woodbury M.E., Srivastava G., et al. The Major Risk Factors for Alzheimer’s Disease: Age, Sex, and Genes Modulate the Microglia Response to Aβ Plaques. Cell Rep. 2019;27:1293–1306. doi: 10.1016/j.celrep.2019.03.099. PubMed DOI PMC

Ising C., Venegas C., Zhang S., Scheiblich H., Schmidt S.V., Vieira-Saecker A., Schwartz S., Albasset S., McManus R.M., Tejera D., et al. NLRP3 inflammasome activation drives tau pathology. Nature. 2019;575:669–673. doi: 10.1038/s41586-019-1769-z. PubMed DOI PMC

Shen Z., Bao X., Wang R. Clinical PET Imaging of Microglial Activation: Implications for Microglial Therapeutics in Alzheimer’s Disease. Front. Aging Neurosci. 2018;10:314. doi: 10.3389/fnagi.2018.00314. PubMed DOI PMC

Yao K., Zu H.B. Microglial polarization: Novel therapeutic mechanism against Alzheimer’s disease. Inflammopharmacology. 2020;28:95–110. doi: 10.1007/s10787-019-00613-5. PubMed DOI

Tondo G., Iaccarino L., Caminiti S.P., Presotto L., Santangelo R., Iannaccone S., Magnani G., Perani D. The combined effects of microglia activation and brain glucose hypometabolism in early-onset Alzheimer’s disease. Alzheimer’s Res. Ther. 2020;12:1–10. doi: 10.1186/s13195-020-00619-0. PubMed DOI PMC

Wang W.-Y., Tan M.-S., Yu J.T., Tan L. Role of pro-inflammatory cytokines released from microglia in Alzheimer’s disease. Ann. Transl. Med. 2015;3:136. PubMed PMC

Stamouli E.C., Politis A.M. Pro-inflammatory cytokines in Alzheimer’s disease. Psychiatriki. 2016;27:264–275. doi: 10.22365/jpsych.2016.274.264. PubMed DOI

Wang M.-M., Miao D., Cao X.-P., Tan L., Tan L. Innate immune activation in Alzheimer’s disease. Ann. Transl. Med. 2018;6:177. doi: 10.21037/atm.2018.04.20. PubMed DOI PMC

Fernández-Arjona M.D.M., Grondona J.M., Fernández-Llebrez P., López-Ávalos M.D. Microglial Morphometric Parameters Correlate With the Expression Level of IL-1β, and Allow Identifying Different Activated Morphotypes. Front. Cell Neurosci. 2019;13:472. doi: 10.3389/fncel.2019.00472. PubMed DOI PMC

Akiyama H., Barger S., Barnum S., Bradt B., Bauer J., Cole G.M., Cooper N.R., Eikelenboom P., Emmerling M., Fiebich B.L., et al. Inflammation and Alzheimer’s disease. Neurobiol. Aging. 2000;21:383–421. doi: 10.1016/S0197-4580(00)00124-X. PubMed DOI PMC

Azizi G., Navabi S.S., Al-Shukaili A., Seyedzadeh M.H., Yazdani R., Mirshafiey A. The Role of Inflammatory Mediators in the Pathogenesis of Alzheimer’s Disease. Sultan Qaboos Univ. Med. J. 2015;15:e305–e316. doi: 10.18295/squmj.2015.15.03.002. PubMed DOI PMC

Chen X.Q., Mobley W.C. Alzheimer Disease Pathogenesis: Insights From Molecular and Cellular Biology Studies of Oligomeric Aβ and Tau Species. Front. Neurosci. 2019;13:659. doi: 10.3389/fnins.2019.00659. PubMed DOI PMC

Heneka M.T., Carson M.J., El Khoury J., Landreth G.E., Brosseron F., Feinstein D.L., Jacobs A.H., Wyss-Coray T., Vitorica J., Ransohoff R.M., et al. Neuroinflammation in Alzheimer’s disease. Lancet Neurol. 2015;14:388–405. doi: 10.1016/S1474-4422(15)70016-5. PubMed DOI PMC

Rios M.A.E., Etoral-Rios D., Efranco-Bocanegra D., Evilleda-Hernández J., Ecampos-Peña V. Inflammatory process in Alzheimer’s Disease. Front. Integr. Neurosci. 2013;7:59. doi: 10.3389/fnint.2013.00059. PubMed DOI PMC

Businaro R., Corsi M., Asprino R., Di Lorenzo C., Laskin D., Corbo R., Ricci S., Pinto A. Modulation of Inflammation as a Way of Delaying Alzheimer’s Disease Progression: The Diet’s Role. Curr. Alzheimer Res. 2018;15:363–380. doi: 10.2174/1567205014666170829100100. PubMed DOI

Skaper S.D., Facci L., Zusso M., Giusti P. An Inflammation-Centric View of Neurological Disease: Beyond the Neuron. Front. Cell Neurosci. 2018;12:72. doi: 10.3389/fncel.2018.00072. PubMed DOI PMC

Duran-Aniotz C., Hetz C. Glucose Metabolism: A Sweet Relief of Alzheimer’s Disease. Curr. Biol. 2016;26:R806–R809. doi: 10.1016/j.cub.2016.07.060. PubMed DOI

Tönnies E., Trushina E. Oxidative Stress, Synaptic Dysfunction, and Alzheimer’s Disease. J. Alzheimer's Dis. 2017;57:1105–1121. doi: 10.3233/JAD-161088. PubMed DOI PMC

Thal D.R., Capetillo-Zarate E., Larionov S., Staufenbiel M., Zurbruegg S., Beckmann N. Capillary cerebral amyloid angiopathy is associated with vessel occlusion and cerebral blood flow disturbances. Neurobiol. Aging. 2009;30:1936–1948. doi: 10.1016/j.neurobiolaging.2008.01.017. PubMed DOI

Potter H., Granic A., Caneus J. Role of Trisomy 21 Mosaicism in Sporadic and Familial Alzheimer’s Disease. Curr. Alzheimer Res. 2015;13:7–17. doi: 10.2174/156720501301151207100616. PubMed DOI PMC

Clare R., King V.G., Wirenfeldt M., Vinters H.V. Synapse loss in dementias. J. Neurosci. Res. 2010;88:2083–2090. doi: 10.1002/jnr.22392. PubMed DOI PMC

Wang W., Zhao F., Ma X., Perry G., Zhu X. Mitochondria dysfunction in the pathogenesis of Alzheimer’s disease: Recent advances. Mol. Neurodegener. 2020;15:1–22. doi: 10.1186/s13024-020-00376-6. PubMed DOI PMC

Norris G.T., Kipnis J. Immune cells and CNS physiology: Microglia and beyond. J. Exp. Med. 2019;216:60–70. doi: 10.1084/jem.20180199. PubMed DOI PMC

Bennett M.L., Bennett F.C., Liddelow S.A., Ajami B., Zamanian J.L., Fernhoff N.B., Mulinyawe S.B., Bohlen C.J., Adil A., Tucker A., et al. New tools for studying microglia in the mouse and human CNS. Proc. Natl. Acad. Sci. USA. 2016;113:E1738–E1746. doi: 10.1073/pnas.1525528113. PubMed DOI PMC

Buttgereit A., Lelios I., Yu X., Vrohlings M., Krakoski N.R., Gautier E.L., Nishinakamura R., Becher B., Greter M. Sall1 is a transcriptional regulator defining microglia identity and function. Nat. Immunol. 2016;17:1397–1406. doi: 10.1038/ni.3585. PubMed DOI

Gomez Perdiguero E., Klapproth K., Schulz C., Busch K., Azzoni E., Crozet L., Garner H., Trouillet C., de Bruijn M.F., Geissmann F., et al. Tissue-resident macrophages originate from yolk-sac-derived erythro-myeloid progenitors. Nature. 2014;518:547–551. doi: 10.1038/nature13989. PubMed DOI PMC

Gosselin D., Link V.M., Romanoski C.E., Fonseca G.J., Eichenfield D.Z., Spann N.J., Stender J.D., Chun H.B., Garner H., Geissmann F., et al. Environment drives selection and function of enhancers controlling tissue-specific macrophage identities. Cell. 2014;159:1327–1340. doi: 10.1016/j.cell.2014.11.023. PubMed DOI PMC

Sheng J., Ruedl C., Karjalainen K. Most tissue-resident macrophages except microglia are derived from fetal hematopoietic stem cells. Immunity. 2015;43:382–393. doi: 10.1016/j.immuni.2015.07.016. PubMed DOI

Hoeffel G., Chen J., Lavin Y., Low D., Almeida F.F., See P., Beaudin A.E., Lum J., Low I., Forsberg E.C., et al. C-Myb+ erythro-myeloid progenitor-derived fetal monocytes give rise to adult tissue-resident macrophages. Immunity. 2015;42:665–678. doi: 10.1016/j.immuni.2015.03.011. PubMed DOI PMC

Ajami B., Bennett J.L., Krieger C., Tetzlaff W., Rossi F.M. Local self-renewal can sustain CNS microglia maintenance and function throughout adult life. Nat. Neurosci. 2007;10:1538–1543. doi: 10.1038/nn2014. PubMed DOI

Tay T.L., Hagemeyer N., Prinz M. The force awakens: Insights into the origin and formation of microglia. Curr. Opin. Neurobiol. 2016;39:30–37. doi: 10.1016/j.conb.2016.04.003. PubMed DOI

Elmore M.R.P., Najafi A.R., Koike M.A., Dagher N.N., Spangenberg E.E., Rice R.A., Kitazawa M., Matusow B., Nguyen H., West B.L., et al. Colony-stimulating factor 1 receptor signaling is necessary for microglia viability, unmasking a microglia progenitor cell in the adult brain. Neuron. 2014;82:380–397. doi: 10.1016/j.neuron.2014.02.040. PubMed DOI PMC

Lenz K.M., Nelson L.H. Microglia and Beyond: Innate Immune Cells As Regulators of Brain Development and Behavioral Function. Front. Immunol. 2018;9:698. doi: 10.3389/fimmu.2018.00698. PubMed DOI PMC

Mildner A., Schmidt H., Nitsche M., Merkler D., Hanisch U.-K., Mack M., Heikenwalder M., Brück W., Priller J., Prinz M., et al. Microglia in the adult brain arise from Ly-6ChiCCR2+ monocytes only under defined host conditions. Nat. Neurosci. 2007;10:1544–1553. doi: 10.1038/nn2015. PubMed DOI

Wohleb E.S., Powell N.D., Godbout J.P., Sheridan J.F. Stress-induced recruitment of bone marrow-derived monocytes to the brain promotes anxiety-like behavior. J. Neurosci. 2013;33:13820–13833. doi: 10.1523/JNEUROSCI.1671-13.2013. PubMed DOI PMC

Sochoka M., Diniz B.S., Leszek J. Inflammatory responses in the CNS: Fried or foe? Mol. Neurobiol. 2017;54:8071–8089. doi: 10.1007/s12035-016-0297-1. PubMed DOI PMC

Tejera D., Heneka M.T. Microglia in Alzheimer’s disease: The good, the bad and the ugly. Curr. Alzheimer Res. 2016;13:370–380. doi: 10.2174/1567205013666151116125012. PubMed DOI

Wyss-Coray T., Rogers J. Inflammation in Alzheimer disease-a brief review of the basic science and clinical literature. Cold Spring Harbor Perspect. Med. 2012;2:a006346. doi: 10.1101/cshperspect.a006346. PubMed DOI PMC

Biber K., Neumann H., Inoue K., Boddeke H.W.G.M. Neuronal ‘On’ and ‘Off’ signals control microglia. Trends Neurosci. 2007;30:596–602. doi: 10.1016/j.tins.2007.08.007. PubMed DOI

Baroja-Mazo A., Martín-Sánchez F., Gomez A.I., Martínez C.M., Amores-Iniesta J., Compan V., Barberà-Cremades M., Yagüe J., Ruiz-Ortiz E., Antón J., et al. The NLRP3 inflammasome is released as a particulate danger signal that amplifies the inflammatory response. Nat. Immunol. 2014;15:738–748. doi: 10.1038/ni.2919. PubMed DOI

Koenigsknecht-Talboo J., Landreth G.E. Microglial phagocytosis induced by fibrillar beta-amyloid and IgGs are differentially regulated by proinflammatory cytokines. J. Neurosci. 2005;25:8240–8249. doi: 10.1523/JNEUROSCI.1808-05.2005. PubMed DOI PMC

Sondag C.M., Dhawan G., Combs C.K. Beta amyloid oligomers and fibrils stimulate differential activation of primary microglia. J. Neuroinflamm. 2009;6 doi: 10.1186/1742-2094-6-1. PubMed DOI PMC

Hommet C., Mondon K., Camus V., Ribeiro M.J., Beaufils E., Arlicot N., Corcia P., Paccalin M., Minier F., Gosselin T., et al. Neuroinflammation and β Amyloid Deposition in Alzheimer’s Disease: In vivo Quantification with Molecular Imaging. Dement. Geriatr. Cogn. Disord. 2014;37:1–18. doi: 10.1159/000354363. PubMed DOI

Nagele R.G., Wegiel J., Venkataraman V., Imaki H., Wang K.C., Wegiel J. Contribution of glial cells to the development of amyloid plaques in Alzheimer’s disease. Neurobiol. Aging. 2004;25:663–674. doi: 10.1016/j.neurobiolaging.2004.01.007. PubMed DOI

Serrano-Pozo A., Mielke M.L., Gómez-Isla T., Betensky R.A., Growdon J.H., Frosch M.P., Hyman B.T. Reactive glia not only associates with plaques but also parallels tangles in Alzheimer’s disease. Am. J. Pathol. 2020;179:1373–1384. doi: 10.1016/j.ajpath.2011.05.047. PubMed DOI PMC

Minter M.R., Taylor J.M., Crack P.J. The contribution of neuroinflammation to amyloid toxicity in Alzheimer’s disease. J. Neurochem. 2016;136:457–474. doi: 10.1111/jnc.13411. PubMed DOI

Bamberger M.E., Harris M.E., McDonald D.R., Husemann J., Landreth G.E. A cell surface receptor complex for fibrillar beta-amyloid mediates microglial activation. J. Neurosci. 2003;23:2665–2674. doi: 10.1523/JNEUROSCI.23-07-02665.2003. PubMed DOI PMC

Ries M., Sastre M. Mechanisms of Aβ clearance and degradation by glial cells. Front. Aging Neurosci. 2016;8:160. doi: 10.3389/fnagi.2016.00160. PubMed DOI PMC

Tahara K., Kim H.-D., Jin J.-J., Maxwell J.A., Li L., Fukuchi K. Role of toll-like receptor signalling in Abeta uptake and clearance. Brain J. Neurol. 2006;129:3006–3019. doi: 10.1093/brain/awl249. PubMed DOI PMC

Wilkinson K., El Khoury J. Microglial scavenger receptors and their roles in the pathogenesis of Alzheimer’s disease. Int. J. Alzheimer's Dis. 2012;2012:489456. doi: 10.1155/2012/489456. PubMed DOI PMC

Hickman S.E., Allison E.K., El Khoury J. Microglial dysfunction and defective beta-amyloid clearance pathways in aging Alzheimer’s disease mice. J. Neurosci. 2008;28:8354–8360. doi: 10.1523/JNEUROSCI.0616-08.2008. PubMed DOI PMC

Thériault P., ElAli A., Rivest S. The dynamics of monocytes and microglia in Alzheimer’s disease. Alzheimer's Res. Ther. 2015;7 doi: 10.1186/s13195-015-0125-2. PubMed DOI PMC

Weiner H.L., Frenkel D. Immunology and immunotherapy of Alzheimer’s disease. Nat. Rev. Immunol. 2006;6:404–416. doi: 10.1038/nri1843. PubMed DOI

Frackowiak J., Wisniewski H.M., Wegiel J., Merz G.S., Iqbal K., Wang K.C. Ultrastructure of the microglia that phagocytose amyloid and the microglia that produce beta-amyloid fibrils. Acta Neuropathol. 1992;84:225–233. doi: 10.1007/BF00227813. PubMed DOI

Krabbe G., Halle A., Matyash V., Rinnenthal J.L., Eom G.D., Bernhardt U., Miller K.R., Prokop S., Kettenmann H., Heppner F.L. Functional impairment of microglia coincides with beta-amyloid deposition in mice with Alzheimer-like pathology. PLoS ONE. 2013;8:e60921. doi: 10.1371/journal.pone.0060921. PubMed DOI PMC

Nagele R.G., D’Andrea M.R., Lee H., Venkataraman V., Wang H.Y. Astrocytes accumulate A beta 42 and give rise to astrocytic amyloid plaques in Alzheimer disease brains. Brain Res. 2003;971:197–209. doi: 10.1016/S0006-8993(03)02361-8. PubMed DOI

Heneka M.T., Sastre M., Dumitrescu-Ozimek L., Hanke A., Dewachter I., Kuiperi C., O’Banion K., Klockgether T., Van Leuven F., Landreth G.E. Acute treatment with the PPARgamma agonist pioglitazone and ibuprofen reduces glial inflammation and Abeta1-42 levels in APPV717I transgenic mice. Brain. 2005;128:1442–1453. doi: 10.1093/brain/awh452. PubMed DOI

Meda L., Baron P., Scarlato G. Glial activation in Alzheimer’s disease: The role of Abeta and its associated proteins. Neurobiol. Aging. 2001;22:885–893. doi: 10.1016/S0197-4580(01)00307-4. PubMed DOI

Morgan D., Gordon M.N., Tan J., Wilcock D., Rojiani A.M. Dynamic complexity of the microglial activation response in transgenic models of amyloid deposition: Implications for Alzheimer therapeutics. J. Neuropathol. Exp. Neurol. 2005;64:743–753. doi: 10.1097/01.jnen.0000178444.33972.e0. PubMed DOI

Tuppo E.E., Arias H.R. The role of inflammation in Alzheimer’s disease. Int. J. Biochem. Cell Biol. 2005;37:289–305. doi: 10.1016/j.biocel.2004.07.009. PubMed DOI

Tan Z.S., Seshadri S. Inflammation in the Alzheimer’s disease cascade: Culprit or innocent bystander? Alzheimer's Res. Ther. 2010;2:6. doi: 10.1186/alzrt29. PubMed DOI PMC

Joshi P.G., Turola E., Ruiz A., Bergami A., Libera D.D., Benussi L., Giussani P., Magnani G., Comi G., Legname G., et al. Microglia convert aggregated amyloid-β into neurotoxic forms through the shedding of microvesicles. Cell Death Differ. 2014;21:582–593. doi: 10.1038/cdd.2013.180. PubMed DOI PMC

Hansen D.V., Hanson J.E., Sheng M. Microglia in Alzheimer’s disease. J. Cell Biol. 2018;217:459–472. doi: 10.1083/jcb.201709069. PubMed DOI PMC

Jiang C., Zou X., Zhu R., Shi Y., Wu Z., Zhao F., Chen L. The correlation between accumulation of amyloid beta with enhanced neuroinflammation and cognitive impairment after intraventricular hemorrhage. J. Neurosurg. 2018;131:54–63. doi: 10.3171/2018.1.JNS172938. PubMed DOI

Edison P., Archer H.A., Gerhard A., Hinz R., Pavese N., Turkheimer F.E., Hammers A., Tai Y.F., Fox N., Kennedy A., et al. Microglia, amyloid, and cognition in Alzheimer’s disease: An [11C](R)PK11195-PET and [11C]PIB-PET study. Neurobiol. Dis. 2008;32:412–419. doi: 10.1016/j.nbd.2008.08.001. PubMed DOI

Okello A., Edison P., Archer H.A., Turkheimer F., Kennedy J., Bullock R., Walker Z., Fox N., Rossor M., Brooks D.J. Microglial activation and amyloid deposition in mild cognitive impairment: A PET study. Neurology. 2009;72:56–62. doi: 10.1212/01.wnl.0000338622.27876.0d. PubMed DOI PMC

Hamelin L., Lagarde J., Dorothée G., Leroy C., Labit M., Comley R.A., De Souza L.C., Corne H., Dauphinot L., Bertoux M., et al. Early and protective microglial activation in Alzheimer’s disease: A prospective study using18F-DPA-714 PET imaging. Brain. 2016;139:1252–1264. doi: 10.1093/brain/aww017. PubMed DOI

Fan Z., Okello A.A., Brooks D.J., Edison P. Longitudinal influence of microglial activation and amyloid on neuronal function in Alzheimer’s disease. Brain. 2015;138:3685–3698. doi: 10.1093/brain/awv288. PubMed DOI

Yokokura M., Mori N., Yagi S., Yoshikawa E., Kikuchi M., Yoshihara Y., Wakuda T., Sugihara G., Takebayashi K., Suda S., et al. In vivo changes in microglial activation and amyloid deposits in brain regions with hypometabolism in Alzheimer’s disease. Eur. J. Nucl. Med. Mol. Imaging. 2010;38:343–351. doi: 10.1007/s00259-010-1612-0. PubMed DOI

Gosztyla M.L., Brothers H.M., Robinson S.R. Alzheimer’s Amyloid-β is an Antimicrobial Peptide: A Review of the Evidence. J. Alzheimer's Dis. 2018;62:1495–1506. doi: 10.3233/JAD-171133. PubMed DOI

Chung W.-S., Allen N.J., Eroglu C. Astrocytes Control Synapse Formation, Function, and Elimination. Cold Spring Harb. Perspect. Biol. 2015;7:a020370. doi: 10.1101/cshperspect.a020370. PubMed DOI PMC

Verkhratsky A., Nedergaard M. Physiology of Astroglia. Physiol. Rev. 2018;98:239–389. doi: 10.1152/physrev.00042.2016. PubMed DOI PMC

Preman P., Alfonso-Triguero M., Alberdi E., Verkhratsky A., Arranz A. Astrocytes in Alzheimer’s Disease: Pathological Significance and Molecular Pathways. Cells. 2021;10:540. doi: 10.3390/cells10030540. PubMed DOI PMC

Sheeler C., Rosa J.-G., Ferro A., McAdams B., Borgenheimer E., Cvetanovic M. Glia in Neurodegeneration: The Housekeeper, the Defender and the Perpetrator. Int. J. Mol. Sci. 2020;21:9188. doi: 10.3390/ijms21239188. PubMed DOI PMC

Gamage R., Wagnon I., Rossetti I., Childs R., Niedermayer G., Chesworth R., Gyengesi E. Cholinergic Modulation of Glial Function During Aging and Chronic Neuroinflammation. Front. Cell. Neurosci. 2020;14:577912. doi: 10.3389/fncel.2020.577912. PubMed DOI PMC

Linnerbauer M., Wheeler M.A., Quintana F.J. Astrocyte Crosstalk in CNS Inflammation. Neuron. 2020;108:608–622. doi: 10.1016/j.neuron.2020.08.012. PubMed DOI PMC

Giovannoni F., Quintana F.J. The role of astrocytes in CNS inflammation. Trends Immunol. 2020;41:805–819. doi: 10.1016/j.it.2020.07.007. PubMed DOI PMC

Hol E.M., Pekny M. Glial fibrillary acidic protein (GFAP) and the astrocyte intermediate filament system in diseases of the central nervous system. Curr. Opin. Cell Biol. 2015;32:121–130. doi: 10.1016/j.ceb.2015.02.004. PubMed DOI

Yang Z., Wang K.K. Glial fibrillary acidic protein: From intermediate filament assembly and gliosis to neurobiomarker. Trends Neurosci. 2015;38:364–374. doi: 10.1016/j.tins.2015.04.003. PubMed DOI PMC

Beach T., McGeer E. Lamina-specific arrangement of astrocytic gliosis and senile plaques in Alzheimer’s disease visual cortex. Brain Res. 1988;463:357–361. doi: 10.1016/0006-8993(88)90410-6. PubMed DOI

Rodríguez J.J., Olabarria M., Chvatal A., Verkhratsky A., Rodr J.J. Astroglia in dementia and Alzheimer’s disease. Cell Death Differ. 2008;16:378–385. doi: 10.1038/cdd.2008.172. PubMed DOI

Verkhratsky A., Zorec R., Parpura V. Stratification of astrocytes in healthy and diseased brain. Brain Pathol. 2017;27:629–644. doi: 10.1111/bpa.12537. PubMed DOI PMC

González-Reyes R.E., Nava-Mesa M.O., Vargas-Sánchez K., Ariza-Salamanca D., Mora-Muñoz L. Involvement of Astrocytes in Alzheimer’s Disease from a Neuroinflammatory and Oxidative Stress Perspective. Front. Mol. Neurosci. 2017;10:427. doi: 10.3389/fnmol.2017.00427. PubMed DOI PMC

Colombo J., Quinn B., Puissant V. Disruption of astroglial interlaminar processes in Alzheimer’s disease. Brain Res. Bull. 2002;58:235–242. doi: 10.1016/S0361-9230(02)00785-2. PubMed DOI

Yeh C.-Y., Vadhwana B., Verkhratsky A., Rodriguez J.J. Early Astrocytic Atrophy in the Entorhinal Cortex of a Triple Transgenic Animal Model of Alzheimer’s Disease. ASN Neuro. 2011;3:e00071. doi: 10.1042/AN20110025. PubMed DOI PMC

Beauquis J., Vinuesa A., Pomilio C., Pavía P., Galván V., Saravia F. Neuronal and Glial Alterations, Increased Anxiety, and Cognitive Impairment before Hippocampal Amyloid Deposition in PDAPP Mice, Model of Alzheimer’s Disease. Hippocampus. 2014;24:257–269. doi: 10.1002/hipo.22219. PubMed DOI

Diniz L.P., Tortelli V., Matias I., Morgado J., Araujo A.P.B., Melo H.M., Da Silva G.S.S., Alves-Leon S.V., De Souza J.M., Ferreira S.T., et al. Astrocyte Transforming Growth Factor Beta 1 Protects Synapses against Aβ Oligomers in Alzheimer’s Disease Model. J. Neurosci. 2017;37:6797–6809. doi: 10.1523/JNEUROSCI.3351-16.2017. PubMed DOI PMC

Iram T., Trudler D., Kain D., Kanner S., Galron R., Vassar R., Barzilai A., Blinder P., Fishelson Z., Frenkel D. Astrocytes from old Alzheimer’s disease mice are impaired in Aβ uptake and in neuroprotection. Neurobiol. Dis. 2016;96:84–94. doi: 10.1016/j.nbd.2016.08.001. PubMed DOI

Polis B., Srikanth K.D., Elliott E., Gil-Henn H., Samson A.O. L-Norvaline Reverses Cognitive Decline and Synaptic Loss in a Murine Model of Alzheimer’s Disease. Neurotherapeutics. 2018;15:1036–1054. doi: 10.1007/s13311-018-0669-5. PubMed DOI PMC

Jones V.C., Atkinson-Dell R., Verkhratsky A., Mohamet L. Aberrant iPSC-Derived Human Astrocytes in Alzheimer’s Disease. Cell Death Dis. 2017;8:e2696. doi: 10.1038/cddis.2017.89. PubMed DOI PMC

Kraft A.W., Hu X., Yoon H., Yan P., Xiao Q., Wang Y., Gil S.C., Brown J., Wilhelmsson U., Restivo J.L., et al. Attenuating astrocyte activation accelerates plaque pathogenesis in APP/PS1 mice. FASEB J. 2013;27:187–198. doi: 10.1096/fj.12-208660. PubMed DOI PMC

Kobayashi E., Nakano M., Kubota K., Himuro N., Mizoguchi S., Chikenji T., Otani M., Mizue Y., Nagaishi K., Fujimiya M. Activated forms of astrocytes with higher GLT-1 expression are associated with cognitive normal subjects with Alzheimer pathology in human brain. Sci. Rep. 2018;8:1–12. doi: 10.1038/s41598-018-19442-7. PubMed DOI PMC

Masliah E., Alford M., DeTeresa R., Mallory M., Hansen L. Deficient glutamate transport is associated with neurodegeneration in Alzheimer’s disease. Ann. Neurol. 1996;40:759–766. doi: 10.1002/ana.410400512. PubMed DOI

Scimemi A., Meabon J.S., Woltjer R.L., Sullivan J.M., Diamond J.S., Cook D.G. Amyloid-β1-42 slows clearance of synaptically released glutamate by mislocalizing astrocytic GLT-1. J. Neurosci. 2013;33:5312–5318. doi: 10.1523/JNEUROSCI.5274-12.2013. PubMed DOI PMC

Vincent A.J., Gasperini R., Foa L., Small D.H. Astrocytes in Alzheimer’s Disease: Emerging Roles in Calcium Dysregulation and Synaptic Plasticity. J. Alzheimer’s Dis. 2010;22:699–714. doi: 10.3233/JAD-2010-101089. PubMed DOI

Ettle B., Schlachetzki J.C.M., Winkler J. Oligodendroglia and myelin in neurodegenerative diseases: More than just bystanders? Mol. Neurobiol. 2016;53:3046–3062. doi: 10.1007/s12035-015-9205-3. PubMed DOI PMC

Mathys H., Davila-Velderrain J., Peng Z., Gao F., Mohammadi S., Young J.Z., Menon M., He L., Abdurrob F., Jiang X., et al. Single-cell transcriptomic analysis of Alzheimer’s disease. Nature. 2019;570:332–337. doi: 10.1038/s41586-019-1195-2. PubMed DOI PMC

Bartzokis G. Age-related myelin breakdown: A developmental model of cognitive decline and Alzheimer’s disease. Neurobiol. Aging. 2004;25:5–18. doi: 10.1016/j.neurobiolaging.2003.03.001. PubMed DOI

Bartzokis G., Lu P.H., Mintz J. Quantifying age-related myelin breakdown with MRI: Novel therapeutic targets for preventing cognitive decline and Alzheimer’s disease. J. Alzheimer's Dis. 2004;6:S53–S59. doi: 10.3233/JAD-2004-6S604. PubMed DOI

Mitew S., Kirkcaldie M.T.K., Halliday G.M., Shepherd C.E., Vickers J.C., Dickson T.C. Focal demyelination in Alzheimer’s disease and transgenic mouse models. Acta Neuropathol. 2010;119:567–577. doi: 10.1007/s00401-010-0657-2. PubMed DOI

Desai M.K., Mastrangelo M.A., Ryan D.A., Sudol K.L., Narrow W.C., Bowers W.J. Early Oligodendrocyte/Myelin Pathology in Alzheimer’s Disease Mice Constitutes a Novel Therapeutic Target. Am. J. Pathol. 2010;177:1422–1435. doi: 10.2353/ajpath.2010.100087. PubMed DOI PMC

Goldmann T., Wieghofer P., Jordão M.J.C., Prutek F., Hagemeyer N., Frenzel K., Amann L., Staszewski O., Kierdorf K., Krueger M., et al. Origin, fate and dynamics of macrophages at central nervous system interfaces. Nat. Immunol. 2016;17:797–805. doi: 10.1038/ni.3423. PubMed DOI PMC

Chinnery H.R., Ruitenberg M.J., McMenamin P.G. Novel characterization of monocyte-derived cell populations in the meninges and choroid plexus and their rates of replenishment in bone marrow chimeric mice. J. Neuropathol. Exp. Neurol. 2010;69:896–909. doi: 10.1097/NEN.0b013e3181edbc1a. PubMed DOI

Prinz M., Priller J. Microglia and brain macrophages in the molecular age: From origin to neuropsychiatric disease. Nat. Rev. Neurosci. 2014;15:300–312. doi: 10.1038/nrn3722. PubMed DOI

Mohamed A., Posse de Chaves E. Aβ internalization by neurons and glia. Int. J. Alzheimer's Dis. 2011;2011:127984. PubMed PMC

Simard A.R., Soulet D., Gowing G., Julien J.-P., Rivest S. Bone Marrow-Derived Microglia Play a Critical Role in Restricting Senile Plaque Formation in Alzheimer’s Disease. Neuron. 2006;49:489–502. doi: 10.1016/j.neuron.2006.01.022. PubMed DOI

Thanopoulou K., Fragkouli A., Stylianopoulou F., Georgopoulos S. Scavenger receptor class B type I (SR-BI) regulates perivascular macrophages and modifies amyloid pathology in an Alzheimer mouse model. Proc. Natl. Acad. Sci. USA. 2010;107:20816–20821. doi: 10.1073/pnas.1005888107. PubMed DOI PMC

Town T., Laouar Y., Pittenger C., Mori T., Szekely C.A., Tan J., Duman R.S., Flavell R.A. Blocking TGF-beta-Smad2/3 innate immune signaling mitigates Alzheimer-like pathology. Nat. Med. 2008;14:681–687. doi: 10.1038/nm1781. PubMed DOI PMC

El Khoury J., Toft M., Hickman S.E., Means T.K., Terada K., Geula C., Luster A.D. Ccr2 deficiency impairs microglial accumulation and accelerates progression of Alzheimer-like disease. Nat. Med. 2007;13:432–438. doi: 10.1038/nm1555. PubMed DOI

Anding A.L., Baehrecke E.H. Cleaning House: Selective Autophagy of Organelles. Dev. Cell. 2017;41:10–22. doi: 10.1016/j.devcel.2017.02.016. PubMed DOI PMC

Li W., He P., Huang Y., Li Y.-F., Lu J., Li M., Kurihara H., Luo Z., Meng T., Onishi M., et al. Selective autophagy of intracellular organelles: Recent research advances. Theranostics. 2021;11:222–256. doi: 10.7150/thno.49860. PubMed DOI PMC

Wang R., Wang G. Autophagy in Mitochondrial Quality Control. Adv. Exp. Med. Biol. 2019;1206:421–434. PubMed

Harper J.W., Ordureau A., Heo J.-M. Building and decoding ubiquitin chains for mitophagy. Nat. Rev. Mol. Cell Biol. 2018;19:93–108. doi: 10.1038/nrm.2017.129. PubMed DOI

Green D.R., Galluzzi L., Kroemer G. Mitochondria and the Autophagy-Inflammation-Cell Death Axis in Organismal Aging. Science. 2011;333:1109–1112. doi: 10.1126/science.1201940. PubMed DOI PMC

Green D.R., Levine B. To be or not to be? How selective autophagy and cell death govern cell fate. Cell. Mol. Life Sci. 2014;157:65–75. doi: 10.1016/j.cell.2014.02.049. PubMed DOI PMC

Desai S., Juncker M., Kim C. Regulation of mitophagy by the ubiquitin pathway in neurodegenerative diseases. Exp. Biol. Med. 2018;243:554–562. doi: 10.1177/1535370217752351. PubMed DOI PMC

Madruga E., Maestro I., Martínez A. Mitophagy Modulation, a New Player in the Race against ALS. Int. J. Mol. Sci. 2021;22:740. doi: 10.3390/ijms22020740. PubMed DOI PMC

Nakahira K., Haspel J.A., Rathinam V.A., Lee S.-J., Dolinay T., Lam H.C., Englert J.A., Rabinovitch M., Cernadas M., Kim H.P., et al. Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome. Nat. Immunol. 2011;12:222–230. doi: 10.1038/ni.1980. PubMed DOI PMC

Shimada K., Crother T.R., Karlin J., Dagvadorj J., Chiba N., Chen S., Ramanujan V.K., Wolf A.J., Vergnes L., Ojcius D.M., et al. Oxidized Mitochondrial DNA Activates the NLRP3 Inflammasome during Apoptosis. Immunity. 2012;36:401–414. doi: 10.1016/j.immuni.2012.01.009. PubMed DOI PMC

Dall’Olio F., Vanhooren V., Chen C.C., Slagboom P.E., Wuhrer M., Franceschi C. N-glycomic biomarkers of biological aging and longevity: A link with inflammaging. Ageing Res. Rev. 2013;12:685–698. doi: 10.1016/j.arr.2012.02.002. PubMed DOI

Feldman N., Rotter-Maskowitz A., Okun E. DAMPs as mediators of sterile inflammation in aging-related pathologies. Ageing Res. Rev. 2015;24:29–39. doi: 10.1016/j.arr.2015.01.003. PubMed DOI

Fang C., Wei X., Wei Y. Mitochondrial DNA in the regulation of innate immune responses. Protein Cell. 2016;7:11–16. doi: 10.1007/s13238-015-0222-9. PubMed DOI PMC

Lamkanfi M., Dixit V.M. Mechanisms and functions of inflammasomes. Cell. 2014;157:1013–1022. doi: 10.1016/j.cell.2014.04.007. PubMed DOI

Vanaja S.K., Rathinam V.A., Fitzgerald K.A. Mechanisms of inflammasome activation: Recent advances and novel insights. Trends Cell Biol. 2015;25:308–315. doi: 10.1016/j.tcb.2014.12.009. PubMed DOI PMC

Mamik M.K., Power C. Inflammasomes in neurological diseases: Emerging pathogenic and therapeutic concepts. Brain. 2017;140:2273–2285. doi: 10.1093/brain/awx133. PubMed DOI

Swanson K.V., Deng M., Ting J.P.-Y. The NLRP3 inflammasome: Molecular activation and regulation to therapeutics. Nat. Rev. Immunol. 2019;19:477–489. doi: 10.1038/s41577-019-0165-0. PubMed DOI PMC

Downs K.P., Nguyen H., Dorfleutner A., Stehlik C. An overview of the non-canonical inflammasome. Mol. Asp. Med. 2020;76:100924. doi: 10.1016/j.mam.2020.100924. PubMed DOI PMC

Horng T. Calcium signaling and mitochondrial destabilization in the triggering of the NLRP3 inflammasome. Trends Immunol. 2014;35:253–261. doi: 10.1016/j.it.2014.02.007. PubMed DOI PMC

Harris J., Hartman M., Roche C., Zeng S.G., O’Shea A., Sharp F.A., Lambe E.M., Creagh E.M., Golenbock D.T., Tschopp J., et al. Autophagy controls IL-1{beta} secretion by targeting pro-IL-1{beta} for degradation. J. Biol. Chem. 2011;286:9587–9597. doi: 10.1074/jbc.M110.202911. PubMed DOI PMC

Lee C., Kim K.H., Cohen P. MOTS-c: A novel mitochondrial-derived peptide regulating muscle and fat metabolism. Free. Radic. Biol. Med. 2016;100:182–187. doi: 10.1016/j.freeradbiomed.2016.05.015. PubMed DOI PMC

Zhai D., Ye Z., Jiang Y., Xu C., Ruan B., Yang Y., Lei X., Xiang A., Lu H., Zhu Z., et al. MOTS-c peptide increases survival and decreases bacterial load in mice infected with MRSA. Mol. Immunol. 2017;92:151–160. doi: 10.1016/j.molimm.2017.10.017. PubMed DOI

Oh Y.K., Bachar A.R., Zacharias D.G., Kim S.G., Wan J., Cobb L.J., Lerman L.O., Cohen P., Lerman A. Humanin preserves endothelial function and prevents atherosclerotic plaque progression in hypercholesterolemic ApoE deficient mice. Atherosclerosis. 2011;219:65–73. doi: 10.1016/j.atherosclerosis.2011.06.038. PubMed DOI PMC

Sreekumar P.G., Ishikawa K., Spee C., Mehta H.H., Wan J., Yen K., Cohen P., Kannan R., Hinton D.R. The Mitochondrial-Derived Peptide Humanin Protects RPE Cells From Oxidative Stress, Senescence, and Mitochondrial Dysfunction. Investig. Opthalmology Vis. Sci. 2016;57:1238–1253. doi: 10.1167/iovs.15-17053. PubMed DOI PMC

Muzumdar R.H., Huffman D.M., Atzmon G., Buettner C., Cobb L.J., Fishman S., Budagov T., Cui L., Einstein F.H., Poduval A., et al. Humanin: A Novel Central Regulator of Peripheral Insulin Action. PLoS ONE. 2009;4:e6334. doi: 10.1371/journal.pone.0006334. PubMed DOI PMC

Halle A., Hornung V., Petzold G.C., Stewart C.R., Monks B.G., Reinheckel T., Fitzgerald K.A., Latz E., Moore K.J., Golenbock D.T. The NALP3 inflammasome is involved in the innate immune response to amyloid-beta. Nat. Immunol. 2008;9:857–865. doi: 10.1038/ni.1636. PubMed DOI PMC

Heneka M.T., Golenbock D.T., Latz E. Innate immunity in Alzheimer’s disease. Nat. Immunol. 2015;16:229–236. doi: 10.1038/ni.3102. PubMed DOI

Kim M.-J., Yoon J.-H., Ryu J.-H. Mitophagy: A balance regulator of NLRP3 inflammasome activation. BMB Rep. 2016;49:529–535. doi: 10.5483/BMBRep.2016.49.10.115. PubMed DOI PMC

Joshi A.U., Minhas P.S., Liddelow S.A., Haileselassie B., Andreasson K.I., Dorn G.W., II, Mochly-Rosen D. Fragmented mitochondria released from microglia trigger A1 astrocytic response and propagate inflammatory neurodegeneration. Nat. Neurosci. 2019;22:1635–1648. doi: 10.1038/s41593-019-0486-0. PubMed DOI PMC

Fairley L.H., Wong J.H., Barron A.M. Mitochondrial Regulation of Microglial Immunometabolism in Alzheimer’s Disease. Front. Immunol. 2021;12:12. doi: 10.3389/fimmu.2021.624538. PubMed DOI PMC

Koellhoffer E.C., McCullough L.D., Ritzel R.M. Old Maids: Aging and Its Impact on Microglia Function. Int. J. Mol. Sci. 2017;18:769. doi: 10.3390/ijms18040769. PubMed DOI PMC

Agrawal I., Jha S. Mitochondrial Dysfunction and Alzheimer’s Disease: Role of Microglia. Front. Aging Neurosci. 2020;120:252. doi: 10.3389/fnagi.2020.00252. PubMed DOI PMC

Baik S.H., Kang S., Lee W., Choi H., Chung S., Kim J.-I., Mook-Jung I. A Breakdown in Metabolic Reprogramming Causes Microglia Dysfunction in Alzheimer’s Disease. Cell Metab. 2019;30:493–507.e6. doi: 10.1016/j.cmet.2019.06.005. PubMed DOI

Afridi R., Kim J.-H., Rahman H., Suk K. Metabolic Regulation of Glial Phenotypes: Implications in Neuron–Glia Interactions and Neurological Disorders. Front. Cell. Neurosci. 2020;14:14. doi: 10.3389/fncel.2020.00020. PubMed DOI PMC

Lauro C., Limatola C. Metabolic Reprograming of Microglia in the Regulation of the Innate Inflammatory Response. Front. Immunol. 2020;11:493. doi: 10.3389/fimmu.2020.00493. PubMed DOI PMC

Afridi R., Lee W.H., Suk K. Microglia Gone Awry: Linking Immunometabolism to Neurodegeneration. Front. Cell Neurosci. 2020;14:246. doi: 10.3389/fncel.2020.00246. PubMed DOI PMC

Pan R.Y., Ma J., Kong X.X., Wang X.F., Li S.S., Qi X.L., Yan Y.H., Cheng J., Liu Q., Jin W., et al. Sodium rutin ameliorates Alzheimer’s disease-like pathology by enhancing microglial amyloid-β clearance. Sci. Adv. 2019;5:eaau6328. doi: 10.1126/sciadv.aau6328. PubMed DOI PMC

Bonda D.J., Wang X., Lee H.-G., Smith M.A., Perry G., Zhu X. Neuronal failure in Alzheimer’s disease: A view through the oxidative stress looking-glass. Neurosci. Bull. 2014;30:243–252. doi: 10.1007/s12264-013-1424-x. PubMed DOI PMC

Dorey E., Chang N., Liu Q.Y., Yang Z., Zhang W. Apolipoprotein E, amyloid-beta, and neuroinflammation in Alzheimer’s disease. Neurosci. Bull. 2014;30:317–330. doi: 10.1007/s12264-013-1422-z. PubMed DOI PMC

Giasson B.I., Duda J.E., Murray I.V.J., Chen Q., Souza J.M., Hurtig H.I., Ischiropoulos H., Trojanowski J.Q., Lee V.M.Y. Oxidative damage linked to neurodegeneration by selective α-synuclein nitration in synucleinopathy lesions. Science. 2000;290:985–989. doi: 10.1126/science.290.5493.985. PubMed DOI

Fischer R., Maier O. Interrelation of oxidative stress and inflammation in neurodegenerative disease: Role of TNF. Oxid. Med. Cell. Longev. 2015;2015 doi: 10.1155/2015/610813. PubMed DOI PMC

Cheeseman K.H., Slater T.F. An Introduction to Free-Radical Biochemistry. Br. Med. Bull. 1993;49:481–493. doi: 10.1093/oxfordjournals.bmb.a072625. PubMed DOI

Marosi K., Bori Z., Hart N., Sárga L., Koltai E., Radák Z., Nyakas C. Long-term exercise treatment reduces oxidative stress in the hippocampus of aging rats. Neurosci. 2012;226:21–28. doi: 10.1016/j.neuroscience.2012.09.001. PubMed DOI

Liguori I., Russo G., Curcio F., Bulli G., Aran L., Della-Morte D., Gargiulo G., Testa G., Cacciatore F., Bonaduce D., et al. Oxidative stress, aging, and diseases. Clin. Interv. Aging. 2018;ume 13:757–772. doi: 10.2147/CIA.S158513. PubMed DOI PMC

Baeeri M., Bahadar H., Rahimifard M., Navaei-Nigjeh M., Khorasani R., Rezvanfar M.A., Gholami M., Abdollahi M. Alpha-Lipoic acid prevents senescence, cell cycle arrest, and inflammatory cues in fibroblasts by inhibiting oxidative stress. Pharm. Res. 2019;141:214–223. doi: 10.1016/j.phrs.2019.01.003. PubMed DOI

Chausse B., Lewen A., Poschet G., Kann O. Selective inhibition of mitochondrial respiratory complexes controls the transition of microglia into a neurotoxic phenotype in situ. Brain, Behav. Immun. 2020;88:802–814. doi: 10.1016/j.bbi.2020.05.052. PubMed DOI

Calvani R., Picca A., Marini F., Biancolillo A., Gervasoni J., Persichilli S., Primiano A., Coelho-Junior H.J., Bossola M., Urbani A., et al. A Distinct Pattern of Circulating Amino Acids Characterizes Older Persons with Physical Frailty and Sarcopenia: Results from the BIOSPHERE Study. Nutrients. 2018;10:1691. doi: 10.3390/nu10111691. PubMed DOI PMC

Disabato D.J., Quan N., Godbout J.P. Neuroinflammation: The devil is in the details. J. Neurochem. 2016;139:136–153. doi: 10.1111/jnc.13607. PubMed DOI PMC

Baierle M., Nascimento S.N., Moro A.M., Brucker N., Freitas F., Gauer B., Durgante J., Bordignon S., Zibetti M., Trentini C.M., et al. Relationship between Inflammation and Oxidative Stress and Cognitive Decline in the Institutionalized Elderly. Oxidative Med. Cell. Longev. 2015;2015:1–12. doi: 10.1155/2015/804198. PubMed DOI PMC

Zuo L., Christofi F.L., Wright V.P., Bao S., Clanton T.L. Lipoxygenase-dependent superoxide release in skeletal muscle. J. Appl. Physiol. 2004;97:661–668. doi: 10.1152/japplphysiol.00096.2004. PubMed DOI

De la Fuente M., Miquel J. An update of the oxidation-inflammation theory of aging: The involvement of the immune system in oxi-inflamm-aging. Curr. Pharm. Des. 2009;15:3003–3026. doi: 10.2174/138161209789058110. PubMed DOI

Daulatzai M.A. Cerebral hypoperfusion and glucose hypometabolism: Key pathophysiological modulators promote neurodegeneration, cognitive impairment, and Alzheimer’s disease. J. Neurosci. Res. 2017;95:943–972. doi: 10.1002/jnr.23777. PubMed DOI

Campisi J., D’Adda Di Fagagna F. Cellular senescence: When bad things happen to good cells. Nat. Rev. Mol. Cell. Biol. 2007;8:729–740. doi: 10.1038/nrm2233. PubMed DOI

Sharpless N.E., Sherr C.J. Forging a signature of in vivo senescence. Nat. Rev. Cancer. 2017;15:397–408. doi: 10.3410/f.725601274.793531867. PubMed DOI

Cuollo L., Antonangeli F., Santoni A., Soriani A. The Senescence-Associated Secretory Phenotype (SASP) in the Challenging Future of Cancer Therapy and Age-Related Diseases. Biology. 2020;9:485. doi: 10.3390/biology9120485. PubMed DOI PMC

Acosta J.C., O’Loghlen A., Banito A., Guijarro M.V., Augert A., Raguz S., Fumagalli M., Da Costa M., Brown C., Popov N., et al. Chemokine Signaling via the CXCR2 Receptor Reinforces Senescence. Cell. 2008;133:1006–1018. doi: 10.1016/j.cell.2008.03.038. PubMed DOI

Coppé J.-P., Desprez P.-Y., Krtolica A., Campisi J. The Senescence-Associated Secretory Phenotype: The Dark Side of Tumor Suppression. Annu. Rev. Pathol. Mech. Dis. 2010;5:99–118. doi: 10.1146/annurev-pathol-121808-102144. PubMed DOI PMC

Neves J., Demaria M., Campisi J., Jasper H. Of Flies, Mice, and Men: Evolutionarily Conserved Tissue Damage Responses and Aging. Dev. Cell. 2015;32:9–18. doi: 10.1016/j.devcel.2014.11.028. PubMed DOI PMC

Borodkina A.V., Deryabin P.I., Giukova A.A., Nikolsky N.N. ‘Social life’ of senescent sells: What is SASP and why study it? Acta Naturae. 2018;10:4–14. doi: 10.32607/20758251-2018-10-1-4-14. PubMed DOI PMC

Moreno-Blas D., Gorostieta-Salas E., Pommer-Alba A., Muciño-Hernández G., Gerónimo-Olvera C., Maciel-Barón L.A., Konigsberg M., Massieu L., Castro-Obregón S. Cortical neurons develop a senescence-like phenotype promoted by dysfunctional autophagy. Aging. 2019;11:6175–6198. doi: 10.18632/aging.102181. PubMed DOI PMC

Acklin S., Zhang M., Du W., Zhao X., Plotkin M., Chang J., Campisi J., Zhou D., Xia F. Depletion of senescent-like neuronal cells alleviates cisplatin-induced peripheral neuropathy in mice. Sci. Rep. 2020;10:1–11. doi: 10.1038/s41598-020-71042-6. PubMed DOI PMC

Schmeer C., Kretz A., Wengerodt D., Stojiljkovic M., Witte O.W. Dissecting Aging and Senescence—Current Concepts and Open Lessons. Cells. 2019;8:1446. doi: 10.3390/cells8111446. PubMed DOI PMC

McHugh D., Gil J. Senescence and aging: Causes, consequences, and therapeutic avenues. J. Cell Biol. 2018;217:65–77. doi: 10.1083/jcb.201708092. PubMed DOI PMC

Wengerodt D., Schmeer C., Witte O.W., Kretz A. Amitosenescence and Pseudomitosenescence: Putative New Players in the Aging Process. Cells. 2019;8:1546. doi: 10.3390/cells8121546. PubMed DOI PMC

Bussian T.J., Aziz A., Meyer C.F., Swenson B.L., Van Deursen J.M., Baker D.J. Clearance of senescent glial cells prevents tau-dependent pathology and cognitive decline. Nat. Cell Biol. 2018;562:578–582. doi: 10.1038/s41586-018-0543-y. PubMed DOI PMC

Musi N., Valentine J.M., Sickora K.R., Baeuerle E., Thompson C.S., Shen Q., Orr M.E. Tau protein aggregation is associated with cellular senescence in the brain. Aging Cell. 2018;17:e12840. doi: 10.1111/acel.12840. PubMed DOI PMC

Walton C.C., Andersen J.K. Unknown fates of (brain) oxidation or UFO: Close encounters with neuronal senescence. Free Radic. Biol. Med. 2019;134:695–701. doi: 10.1016/j.freeradbiomed.2019.01.012. PubMed DOI

Zhang P., Kishimoto Y., Grammatikakis I., Gottimukkala K., Cutler R.G., Zhang S., Abdelmohsen K., Bohr V.A., Sen J.M., Gorospe M., et al. Senolytic therapy alleviates Aβ-associated oligodendrocyte progenitor cell senescence and cognitive deficits in an Alzheimer’s disease model. Nat. Neurosci. 2019;22:719–728. doi: 10.1038/s41593-019-0372-9. PubMed DOI PMC

Basisty N., Kale A., Jeon O.H., Kuehnemann C., Payne T., Rao C., Holtz A., Shah S., Sharma V., Ferrucci L., et al. A proteomic atlas of senescence-associated secretomes for aging biomarker development. PLoS Biol. 2020;18:e3000599. doi: 10.1371/journal.pbio.3000599. PubMed DOI PMC

Hernandez-Segura A., de Jong T.V., Melov S., Guryev V., Campisi J., Demaria M. Unmasking transcriptional heterogeneity in senescent cells. Curr. Biol. 2017;27:2652–2660.e4. doi: 10.1016/j.cub.2017.07.033. PubMed DOI PMC

Fafián-Labora J.A., O’Loghlen A. Classical and Nonclassical Intercellular Communication in Senescence and Ageing. Trends Cell Biol. 2020;30:628–639. doi: 10.1016/j.tcb.2020.05.003. PubMed DOI

Herranz N., Gil J. Mechanisms and functions of cellular senescence. J. Clin. Investig. 2018;128:1238–1246. doi: 10.1172/JCI95148. PubMed DOI PMC

Song P., An J., Zou M.-H. Immune Clearance of Senescent Cells to Combat Ageing and Chronic Diseases. Cells. 2020;9:671. doi: 10.3390/cells9030671. PubMed DOI PMC

Prata L.G.L., Ovsyannikova I.G., Tchkonia T., Kirkland J.L. Senescent cell clearance by the immune system: Emerging therapeutic opportunities. Semin. Immunol. 2018;40:101275. doi: 10.1016/j.smim.2019.04.003. PubMed DOI PMC

Ferrucci L., Fabbri E. Inflammageing: Chronic inflammation in ageing, cardiovascular disease, and frailty. Nat. Rev. Cardiol. 2018;15:505–522. doi: 10.1038/s41569-018-0064-2. PubMed DOI PMC

Demirci D., Dayanc B., Mazi F., Senturk S. The Jekyll and Hyde of Cellular Senescence in Cancer. Cells. 2021;10:208. doi: 10.3390/cells10020208. PubMed DOI PMC

Walton C.C., Begelman D., Nguyen W., Andersen J.K. Senescence as an Amyloid Cascade: The Amyloid Senescence Hypothesis. Front. Cell. Neurosci. 2020;14:14. doi: 10.3389/fncel.2020.00129. PubMed DOI PMC

Carreno G., Guiho R., Martinez-Barbera J.P. Cell senescence in neuropathology: A focus on neurodegeneration and tumours. Neuropathol. Appl. Neurobiol. 2021;47:359–378. doi: 10.1111/nan.12689. PubMed DOI PMC

Bhat R., Crowe E.P., Bitto A., Moh M., Katsetos C.D., Garcia F.U., Johnson F.B., Trojanowski J.Q., Sell C., Torres C. Astrocyte senescence as a component of Alzheimer’s disease. PLoS ONE. 2012;7:45069. doi: 10.1371/journal.pone.0045069. PubMed DOI PMC

Pertusa M., García-Matas S., Rodríguez-Farré E., Sanfeliu C., Cristòfol R. Astrocytes aged in vitro show a decreased neuroprotective capacity. J. Neurochem. 2007;101:794–805. doi: 10.1111/j.1471-4159.2006.04369.x. PubMed DOI

Mansour H., Chamberlain C.G., Weible M.W.I., Hughes S., Chu Y., Chan-Ling T. Aging-related changes in astrocytes in the rat retina: Imbalance between cell proliferation and cell death reduces astrocyte availability. Aging Cell. 2008;7:526–540. doi: 10.1111/j.1474-9726.2008.00402.x. PubMed DOI

Lee J.-H., Yu W.H., Kumar A., Lee S., Mohan P.S., Peterhoff C.M., Wolfe D.M., Martinez-Vicente M., Massey A.C., Sovak G., et al. Lysosomal Proteolysis and Autophagy Require Presenilin 1 and Are Disrupted by Alzheimer-Related PS1 Mutations. Cell. 2010;141:1146–1158. doi: 10.1016/j.cell.2010.05.008. PubMed DOI PMC

Evans R.J., Wyllie F.S., Wynford-Thomas D., Kipling D., Jones C.J. A P53-dependent, telomere-independent proliferative life span barrier in human astrocytes consistent with the molecular genetics of glioma development. Cancer Res. 2003;63:4854–4861. PubMed

Bitto A., Sell C., Crowe E., Lorenzini A., Malaguti M., Hrelia S., Torres C. Stress-induced senescence in human and rodent astrocytes. Exp. Cell Res. 2010;316:2961–2968. doi: 10.1016/j.yexcr.2010.06.021. PubMed DOI

Oddo S.C.A., Shepherd J.D., Murphy M.P., Golde T.E., Kayed R., Metherate R., Mattson M.P., Akbari Y., LaFerla F.M. Triple-transgenic model of Alzheimer’s disease with plaques and tangles: Intracellular Abeta and synaptic dysfunction. Neuron. 2003;39:409–421. doi: 10.1016/S0896-6273(03)00434-3. PubMed DOI

Vanzulli I., Papanikolaou M., De-La-Rocha I.C., Pieropan F., Rivera A.D., Gomez-Nicola D., Verkhratsky A., Rodríguez J.J., Butt A.M. Disruption of oligodendrocyte progenitor cells is an early sign of pathology in the triple transgenic mouse model of Alzheimer’s disease. Neurobiol. Aging. 2020;94:130–139. doi: 10.1016/j.neurobiolaging.2020.05.016. PubMed DOI PMC

Luterman J.D., Haroutunian V., Yemul S., Ho L., Purohit D., Aisen P.S., Mohs R., Pasinetti G.M. Cytokine gene expression as a function of the clinical progression of Alzheimer disease dementia. Arch Neurol. 2000;57:1153–1160. doi: 10.1001/archneur.57.8.1153. PubMed DOI

Gruol D.L. IL-6 regulation of synaptic function in the CNS. Neuropharmacology. 2015;96:42–54. doi: 10.1016/j.neuropharm.2014.10.023. PubMed DOI PMC

Iannello A., Thompson T.W., Ardolino M., Lowe S.W., Raulet D.H. p53-dependent chemokine production by senescent tumor cells supports NKG2D-dependent tumor elimination by natural killer cells. J. Exp. Med. 2013;210:2057–2069. doi: 10.1084/jem.20130783. PubMed DOI PMC

Sagiv A., Burton D.G.A., Moshayev Z., Vadai E., Wensveen F., Ben-Dor S., Golani O., Polic B., Krizhanovsky V. NKG2D ligands mediate immunosurveillance of senescent cells. Aging. 2016;8:328–344. doi: 10.18632/aging.100897. PubMed DOI PMC

Pereira B.I., Devine O.P., Vukmanovic-Stejic M., Chambers E.S., Subramanian P., Patel N., Virasami A., Sebire N.J., Kinsler V., Valdovinos A., et al. Senescent cells evade immune clearance via HLA-E-mediated NK and CD8+ T cell inhibition. Nat. Commun. 2019;10:1–13. doi: 10.1038/s41467-019-10335-5. PubMed DOI PMC

Muñoz-Espín D., Cañamero M., Maraver A., Gómez-López G., Contreras J., Murillo-Cuesta S., Rodríguez-Baeza A., Varela-Nieto I., Ruberte J., Collado M., et al. XProgrammed cell senescence during mammalian embryonic development. Cell. 2013;155:1104–1118. doi: 10.1016/j.cell.2013.10.019. PubMed DOI

Kang T.-W., Yevsa T., Woller N., Hoenicke L., Wuestefeld T., Dauch D., Hohmeyer A., Gereke M., Rudalska R., Potapova A., et al. Senescence surveillance of pre-malignant hepatocytes limits liver cancer development. Nature. 2011;479:547–551. doi: 10.1038/nature10599. PubMed DOI

Krizhanovsky V., Yon M., Dickins R.A., Hearn S., Simon J., Miething C., Yee H., Zender L., Lowe S.W. Senescence of Activated Stellate Cells Limits Liver Fibrosis. Cell. 2008;134:657–667. doi: 10.1016/j.cell.2008.06.049. PubMed DOI PMC

Galea I., Bechmann I., Perry V.H. What is immune privilege (not)? Trends Immunol. 2007;28:12–18. doi: 10.1016/j.it.2006.11.004. PubMed DOI

Korin B., Ben-Shaanan T.L., Schiller M., Dubovik T., Azulay-Debby H., Boshnak N.T., Koren T., Rolls A. High-dimensional, single-cell characterization of the brain’s immune compartment. Nat. Neurosci. 2017;20:1300–1309. doi: 10.1038/nn.4610. PubMed DOI

Benakis C., Llovera G., Liesz A. The meningeal and choroidal infiltration routes for leukocytes in stroke. Ther. Adv. Neurol. Disord. 2018;11:11. doi: 10.1177/1756286418783708. PubMed DOI PMC

Ardura-Fabregat A., Boddeke E.W.G.M., Boza-Serrano A., Brioschi S., Castro-Gomez S., Ceyzériat K., Dansokho C., Dierkes T., Gelders G., Heneka M.T., et al. Targeting Neuroinflammation to Treat Alzheimer’s Disease. CNS Drugs. 2017;31:1057–1082. doi: 10.1007/s40263-017-0483-3. PubMed DOI PMC

Gorlé N., Van Cauwenberghe C., Libert C., Vandenbroucke R.E. The effect of aging on brain barriers and the consequences for Alzheimer’s disease development. Mamm. Genome. 2016;27:407–420. doi: 10.1007/s00335-016-9637-8. PubMed DOI

Sweeney M.D., Sagare A.P., Zlokovic B.V. Blood–brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders. Nat. Rev. Neurol. 2018;14:133–150. doi: 10.1038/nrneurol.2017.188. PubMed DOI PMC

Nation D.A., Sweeney M.D., Montagne A., Sagare A.P., D’Orazio L.M., Pachicano M., Sepehrband F., Nelson A.R., Buennagel D.P., Harrington M.G., et al. Blood–brain barrier breakdown is an early biomarker of human cognitive dysfunction. Nat. Med. 2019;25:270–276. doi: 10.1038/s41591-018-0297-y. PubMed DOI PMC

van de Haar H.J., Burgmans S., Jansen J.F., van Osch M.J., van Buchem M.A., Muller M., Hofman P.A., Verhey F.R., Backes W.H. Blood-Brain Barrier Leakage in Patients with Early Alzheimer Disease. Radiology. 2016;281:527–535. doi: 10.1148/radiol.2016152244. PubMed DOI

McManus R.M., Mills K.H., Lynch M.A. T cells—protective or pathogenic in Alzheimer’s disease? J. Neuroimmune Pharmacol. 2015;10:547–560. doi: 10.1007/s11481-015-9612-2. PubMed DOI

Yu J.T., Xu W., Tan C.C., Andrieu S., Suckling J., Evangelou E., Pan A., Zhang C., Jia J., Feng L., et al. Evidence-based prevention of Alzheimer’s disease: Systematic review and meta-analysis of 243 observational prospective studies and 153 randomised controlled trials. J. Neurol. Neurosurg. Psychiatry. 2020;111:1201–1209. doi: 10.1136/jnnp-2019-321913. PubMed DOI PMC

Kivipelto M., Mangialasche F., Ngandu T. Lifestyle interventions to prevent cognitive impairment, dementia and Alzheimer disease. Nat. Rev. Neurol. 2018;14:653–666. doi: 10.1038/s41582-018-0070-3. PubMed DOI

Nguyen T.T., Ta Q.T.H., Nguyen T.K.O., Nguyen T.T.D., Giau V.V. Type 3 Diabetes and Its Role Implications in Alzheimer’s Disease. Int. J. Mol. Sci. 2020;21:3165. doi: 10.3390/ijms21093165. PubMed DOI PMC

Kandimalla R., Thirumala V., Reddy P.H. Is Alzheimer’s disease a Type 3 Diabetes? A critical appraisal. Biochim. Biophys. Acta (BBA) Mol. Basis Dis. 2017;1863:1078–1089. doi: 10.1016/j.bbadis.2016.08.018. PubMed DOI PMC

Sun S., Ji Y., Kersten S., Qi L. Mechanisms of Inflammatory Responses in Obese Adipose Tissue. Annu. Rev. Nutr. 2012;32:261–286. doi: 10.1146/annurev-nutr-071811-150623. PubMed DOI PMC

Mraz M., Haluzik M. The role of adipose tissue immune cells in obesity and low-grade inflammation. J. Endocrinol. 2014;222:R113–R127. doi: 10.1530/JOE-14-0283. PubMed DOI

Schenk S., Saberi M., Olefsky J.M. Insulin sensitivity: Modulation by nutrients and inflammation. J. Clin. Investig. 2008;118:2992–3002. doi: 10.1172/JCI34260. PubMed DOI PMC

Chait A., den Hartigh L.J. Adipose Tissue Distribution, Inflammation and Its Metabolic Consequences, Including Diabetes and Cardiovascular Disease. Front. Cardiovasc. Med. 2020;7:22. doi: 10.3389/fcvm.2020.00022. PubMed DOI PMC

Nguyen T.T., Ta Q.T.H., Nguyen T.T.D., Le T.T., Vo V.G. Role of Insulin Resistance in the Alzheimer’s Disease Progression. Neurochem. Res. 2020;45:1481–1491. doi: 10.1007/s11064-020-03031-0. PubMed DOI

Bahniwal M., Little J.P., Klegeris A. High Glucose Enhances Neurotoxicity and Inflammatory Cytokine Secretion by Stimulated Human Astrocytes. Curr. Alzheimer Res. 2017;14:731–741. doi: 10.2174/1567205014666170117104053. PubMed DOI

Anjum I., Fayyaz M., Wajid A., Sohail W., Ali A. Does Obesity Increase the Risk of Dementia: A Literature Review. Cureus. 2018;10:e2660. doi: 10.7759/cureus.2660. PubMed DOI PMC

Flores-Dorantes M.T., Díaz-López Y.E., Gutiérrez-Aguilar R. Environment and Gene Association With Obesity and Their Impact on Neurodegenerative and Neurodevelopmental Diseases. Front. Neurosci. 2020;28:863. doi: 10.3389/fnins.2020.00863. PubMed DOI PMC

Batatinha H.A., Biondo L.A., Lira F.S., Castell L.M., Rosa-Neto J.C. Nutrients, immune system, and exercise: Where will it take us? Nutrition. 2019;61:151–156. doi: 10.1016/j.nut.2018.09.019. PubMed DOI

Nieman D.C., Lila M.A., Gillitt N.D. Immunometabolism: A Multi-Omics Approach to Interpreting the Influence of Exercise and Diet on the Immune System. Annu. Rev. Food Sci. Technol. 2019;10:341–363. doi: 10.1146/annurev-food-032818-121316. PubMed DOI

Simpson R.J., Lowder T.W., Spielmann G., Bigley A.B., LaVoy E.C., Kunz H. Exercise and the aging immune system. Ageing Res. Rev. 2012;11:404–420. doi: 10.1016/j.arr.2012.03.003. PubMed DOI

Ostrowski K., Rohde T., Zacho M., Asp S., Pedersen B.K. Evidence that interleukin-6 is produced in human skeletal muscle during prolonged running. J. Physiol. 1998;508:949–953. doi: 10.1111/j.1469-7793.1998.949bp.x. PubMed DOI PMC

Ma L., Zhang H., Yin Y.-L., Guo W.-Z., Ma Y.-Q., Wang Y.-B., Shu C., Dong L.-Q. Role of interleukin-6 to differentiate sepsis from non-infectious systemic inflammatory response syndrome. Cytokine. 2016;88:126–135. doi: 10.1016/j.cyto.2016.08.033. PubMed DOI

Febbraio M.A., Hiscock N., Sacchetti M., Fischer C.P., Pedersen B.K. Interleukin-6 Is a Novel Factor Mediating Glucose Homeostasis During Skeletal Muscle Contraction. Diabetes. 2004;53:1643–1648. doi: 10.2337/diabetes.53.7.1643. PubMed DOI

Petersen E.W., Carey A.L., Sacchetti M., Steinberg G.R., Macaulay S.L., Febbraio M.A., Pedersen B.K. Acute IL-6 treatment increases fatty acid turnover in elderly humans in vivo and in tissue culture in vitro. Am. J. Physiol. Metab. 2005;288:E155–E162. doi: 10.1152/ajpendo.00257.2004. PubMed DOI

Neto J.C., Silveira L.S. Endurance Exercise Mitigates Immunometabolic Adipose Tissue Disturbances in Cancer and Obesity. Int. J. Mol. Sci. 2020;21:9745. doi: 10.3390/ijms21249745. PubMed DOI PMC

Kwilasz A., Grace P., Serbedzija P., Maier S., Watkins L. The therapeutic potential of interleukin-10 in neuroimmune diseases. Neuropharmacology. 2015;96:55–69. doi: 10.1016/j.neuropharm.2014.10.020. PubMed DOI PMC

Lobo-Silva D., Carriche G.M., Gil Castro A., Roque S., Saraiva M. Balancing the immune response in the brain: IL-10 and its regulation. J. Neuroinflamm. 2016;13:1–10. doi: 10.1186/s12974-016-0763-8. PubMed DOI PMC

Littlefield A.M., Setti S.E., Priester C., Kohman R.A. Voluntary exercise attenuates LPS-induced reductions in neurogenesis and increases microglia expression of a proneurogenic phenotype in aged mice. J. Neuroinflamm. 2015;12:1–12. doi: 10.1186/s12974-015-0362-0. PubMed DOI PMC

Rêgo M.L., Cabral D.A., Costa E.C., Fontes E.B. Physical Exercise for Individuals with Hypertension: It Is Time to Emphasize its Benefits on the Brain and Cognition. Clin. Med. Insights Cardiol. 2019;13:1179546819839411. doi: 10.1177/1179546819839411. PubMed DOI PMC

Di Liegro C.M., Schiera G., Proia P., Di Liegro I. Physical Activity and Brain Health. Genes. 2019;10:720. doi: 10.3390/genes10090720. PubMed DOI PMC

O’Toole P.W., Jeffery I.B. Gut microbiota and aging. Science. 2015;350:1214–1215. doi: 10.1126/science.aac8469. PubMed DOI

Vemuri R., Gundamaraju R., Shastri M.D., Shukla S.D., Kalpurath K., Ball M., Tristram S., Shankar E.M., Ahuja K., Eri R. Gut Microbial Changes, Interactions, and Their Implications on Human Lifecycle: An Ageing Perspective. BioMed Res. Int. 2018;2018:1–13. doi: 10.1155/2018/4178607. PubMed DOI PMC

Radjabzadeh D., Boer C.G., Beth S.A., Van Der Wal P., Jong J.C.K.-D., Jansen M.A.E., Konstantinov S.R., Peppelenbosch M.P., Hays J.P., Jaddoe V.W.V., et al. Diversity, compositional and functional differences between gut microbiota of children and adults. Sci. Rep. 2020;10:1–13. doi: 10.1038/s41598-020-57734-z. PubMed DOI PMC

Claesson M.J., Jeffery I.B., Conde S., Power S.E., O’Connor E.M., Cusack S., Harris H.M.B., Coakley M., Lakshminarayanan B., O’Sullivan O., et al. Gut microbiota composition correlates with diet and health in the elderly. Nature. 2012;488:178–184. doi: 10.1038/nature11319. PubMed DOI

Jiang C., Li G., Huang P., Liu Z., Zhao B. The Gut Microbiota and Alzheimer’s Disease. J. Alzheimer's Dis. 2017;58:1–15. doi: 10.3233/JAD-161141. PubMed DOI

Bostanciklioğlu M. The role of gut microbiota in pathogenesis of Alzheimer’s disease. J. Appl. Microbiol. 2019;127:954–967. doi: 10.1111/jam.14264. PubMed DOI

Talwar P., Kushwaha S., Gupta R., Agarwal R. Systemic Immune Dyshomeostasis Model and Pathways in Alzheimer’s Disease. Front. Aging Neurosci. 2019;11:290. doi: 10.3389/fnagi.2019.00290. PubMed DOI PMC

Bonaz B., Bazin T., Pellissier S. The Vagus Nerve at the Interface of the Microbiota-Gut-Brain Axis. Front. Neurosci. 2018;12:49. doi: 10.3389/fnins.2018.00049. PubMed DOI PMC

Muller P.A., Schneeberger M., Matheis F., Wang P., Kerner Z., Ilanges A., Pellegrino K., Del Mármol J., Castro T.B.R., Furuichi M., et al. Microbiota modulate sympathetic neurons via a gut–brain circuit. Nat. Cell Biol. 2020;583:441–446. doi: 10.1038/s41586-020-2474-7. PubMed DOI PMC

Wang X., Sun G., Feng T., Zhang J., Huang X., Wang T., Xie Z., Chu X., Yang J., Wang H., et al. Sodium oligomannate therapeutically remodels gut microbiota and suppresses gut bacterial amino acids-shaped neuroinflammation to inhibit Alzheimer’s disease progression. Cell Res. 2019;29:787–803. doi: 10.1038/s41422-019-0216-x. PubMed DOI PMC

Rea K., Dinan T.G., Cryan J.F. The microbiome: A key regulator of stress and neuroinflammation. Neurobiol. Stress. 2016;4:23–33. doi: 10.1016/j.ynstr.2016.03.001. PubMed DOI PMC

Chen J., Buchanan J.B., Sparkman N.L., Godbout J.P., Freund G.G., Johnson R.W. Neuroinflammation and disruption in working memory in aged mice after acute stimulation of the peripheral innate immune system. Brain Behav. Immun. 2008;22:301–311. doi: 10.1016/j.bbi.2007.08.014. PubMed DOI PMC

McManus R.M., Heneka M.T. Role of neuroinflammation in neurodegeneration: New insights. Alzheimer's Res. Ther. 2017;9:14. doi: 10.1186/s13195-017-0241-2. PubMed DOI PMC

Carpanini S.M., Torvell M., Morgan B.P. Therapeutic Inhibition of the Complement System in Diseases of the Central Nervous System. Front. Immunol. 2019;10:362. doi: 10.3389/fimmu.2019.00362. PubMed DOI PMC

Morgan B.P. Complement in the pathogenesis of Alzheimer’s disease. Semin. Immunopathol. 2018;40:113–124. doi: 10.1007/s00281-017-0662-9. PubMed DOI PMC

Tenner A.J., Stevens B., Woodruff T.M. New tricks for an ancient system: Physiological and pathological roles of complement in the CNS. Mol. Immunol. 2018;102:3–13. doi: 10.1016/j.molimm.2018.06.264. PubMed DOI PMC

Wu T., Dejanovic B., Gandham V.D., Gogineni A., Edmonds R., Schauer S., Srinivasan K., Huntley M.A., Wang Y., Wang T.M., et al. Complement C3 is activated in human AD brain and is required for neurodegeneration in mouse models of amyloidosis and tauopathy. Cell Rep. 2019;28:e6-2123. doi: 10.1016/j.celrep.2019.07.060. PubMed DOI

Montagne A., Barnes S.R., Sweeney M.D., Halliday M.R., Sagare A.P., Zhao Z., Toga A.W., Jacobs R.E., Liu C.Y., Amezcua L., et al. Blood-Brain Barrier Breakdown in the Aging Human Hippocampus. Neuron. 2015;85:296–302. doi: 10.1016/j.neuron.2014.12.032. PubMed DOI PMC

Varatharaj A., Galea I. The blood-brain barrier in systemic inflammation. Brain Behav. Immun. 2017;60:1–12. doi: 10.1016/j.bbi.2016.03.010. PubMed DOI

Takeda S., Sato N., Morishita R. Systemic inflammation, blood-brain barrier vulnerability and cognitive/non-cognitive symptoms in Alzheimer disease: Relevance to pathogenesis and therapy. Front. Aging Neurosci. 2014;6:171. doi: 10.3389/fnagi.2014.00171. PubMed DOI PMC

Jaeger L.B., Dohgu S., Sultana R., Lynch J.L., Owen J.B., Erickson M.A., Shah G.N., Price T.O., Fleegal-Demotta M.A., Butterfield D.A., et al. Lipopolysaccharide alters the blood-brain barrier transport of amyloid beta protein: A mechanism for inflammation in the progression of Alzheimer’s disease. Brain Behav. Immun. 2009;23:507–517. doi: 10.1016/j.bbi.2009.01.017. PubMed DOI PMC

Propson N.E., Roy E.R., Litvinchuk A., Köhl J., Zheng H. Endothelial C3a receptor mediates vascular inflammation and blood-brain barrier permeability during aging. J. Clin. Investig. 2021;131:131. doi: 10.1172/JCI140966. PubMed DOI PMC

Bhatia K., Ahmad S., Kindelin A., Ducruet A.F. Complement C3a receptor-mediated vascular dysfunction: A complex interplay between aging and neurodegeneration. J. Clin. Investig. 2021;131:e144348. doi: 10.1172/JCI144348. PubMed DOI PMC

Liddelow S.A., Guttenplan K.A., Clarke L.E., Bennett F.C., Bohlen C.J., Schirmer L., Bennett M.L., Münch A.E., Chung W.-S., Peterson T.C., et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature. 2017;541:481–487. doi: 10.1038/nature21029. PubMed DOI PMC

Perez-Nievas B.G., Serrano-Pozo A. Deciphering the Astrocyte Reaction in Alzheimer’s Disease. Front. Aging Neurosci. 2018;10:114. doi: 10.3389/fnagi.2018.00114. PubMed DOI PMC

Seol Y., Ki S., Ryu H.L., Chung S., Lee J., Ryu H. How Microglia Manages Non-cell Autonomous Vicious Cycling of Aβ Toxicity in the Pathogenesis of AD. Front. Mol. Neurosci. 2020;13:13. doi: 10.3389/fnmol.2020.593724. PubMed DOI PMC

Henstridge C.M., Hyman B.T., Spires-Jones T.L. Beyond the neuron–cellular interactions early in Alzheimer disease pathogenesis. Nat. Rev. Neurosci. 2019;20:94–108. doi: 10.1038/s41583-018-0113-1. PubMed DOI PMC

Fullerton J.N., Gilroy D.W. Resolution of inflammation: A new therapeutic frontier. Nat. Rev. Drug Discov. 2016;15:551–567. doi: 10.1038/nrd.2016.39. PubMed DOI

Probert L. TNF and its receptors in the CNS: The essential, the desirable and the deleterious effects. Neuroscience. 2015;302:2–22. doi: 10.1016/j.neuroscience.2015.06.038. PubMed DOI

Steeland S., Vandenbroucke R.E.J. Choroid plexus tumor necrosis factor receptor 1: A new neuroinflammatory piece of the complex Alzheimer’s disease puzzle. Neural Regen Res. 2019;14:1144–1147. PubMed PMC

Belarbi K., Jopson T., Tweedie D., Arellano C., Luo W., Greig N.H., Rosi S. TNF-α protein synthesis inhibitor restores neuronal function and reverses cognitive deficits induced by chronic neuroinflammation. J. Neuroinflamm. 2012;9:23. doi: 10.1186/1742-2094-9-23. PubMed DOI PMC

Olmos G., Lladó J. Tumor necrosis factor alpha: A link between neuroinflammation and excitotoxicity. Mediat. Inflamm. 2014;2014:861231. doi: 10.1155/2014/861231. PubMed DOI PMC

Chang R., Yee K.L., Sumbria R.K. Tumor necrosis factor α Inhibition for Alzheimer’s Disease. J. Cent. Nerv. Syst. Dis. 2017;9:1179573517709278. doi: 10.1177/1179573517709278. PubMed DOI PMC

Paouri E., Tzara O., Kartalou G.-I., Zenelak S., Georgopoulos S. Peripheral Tumor Necrosis Factor-Alpha (TNF-α) Modulates Amyloid Pathology by Regulating Blood-Derived Immune Cells and Glial Response in the Brain of AD/TNF Transgenic Mice. J. Neurosci. 2017;37:5155–5171. doi: 10.1523/JNEUROSCI.2484-16.2017. PubMed DOI PMC

Paouri E., Tzara O., Zenelak S., Georgopoulos S. Genetic Deletion of Tumor Necrosis Factor-α Attenuates Amyloid-β Production and Decreases Amyloid Plaque Formation and Glial Response in the 5XFAD Model of Alzheimer’s Disease. J. Alzheimer’s Dis. 2017;60:165–181. doi: 10.3233/JAD-170065. PubMed DOI

Steeland S., Gorlé N., VandenDriessche C., Balusu S., Brkic M., Van Cauwenberghe C., Van Imschoot G., Van Wonterghem E., De Rycke R., Kremer A., et al. Counteracting the effects of TNF receptor-1 has therapeutic potential in Alzheimer’s disease. EMBO Mol. Med. 2018;10:e8300. doi: 10.15252/emmm.201708300. PubMed DOI PMC

Lapadula G., Marchesoni A., Armuzzi A., Blandizzi C., Caporali R., Chimenti S., Cimaz R., Cimino L., Gionchetti P., Girolomoni G., et al. Adalimumab in the Treatment of Immune-Mediated Diseases. Int. J. Immunopathol. Pharmacol. 2014;27:33–48. doi: 10.1177/03946320140270S103. PubMed DOI

Decourt B., Drumm-Gurnee D., Wilson J., Jacobson S., Belden C., Sirrel S., Ahmadi M., Shill H., Powell J., Walker A., et al. Poor Safety and Tolerability Hamper Reaching a Potentially Therapeutic Dose in the Use of Thalidomide for Alzheimer’s disease: Results from a Double-Blind, Placebo-Controlled Trial. Curr. Alzheimer Res. 2017;14:1. doi: 10.2174/1567205014666170117141330. PubMed DOI PMC

Park J., Lee S.-Y., Shon J., Kim K., Lee H.J., Kim K.A., Lee B.-Y., Oh S.-H., Kim N.K., Kim O.J. Adalimumab improves cognitive impairment, exerts neuroprotective effects and attenuates neuroinflammation in an Aβ1-40-injected mouse model of Alzheimer’s disease. Cytotherapy. 2019;21:671–682. doi: 10.1016/j.jcyt.2019.04.054. PubMed DOI

Anwar S., Rivest S. Alzheimer’s disease: Microglia targets and their modulation to promote amyloid phagocytosis and mitigate neuroinflammation. Expert Opin. Ther. Targets. 2020;24:331–344. doi: 10.1080/14728222.2020.1738391. PubMed DOI

Zhou M., Xu R., Kaelber D.C., Gurney M.E. Tumor Necrosis Factor (TNF) blocking agents are associated with lower risk for Alzheimer’s disease in patients with rheumatoid arthritis and psoriasis. PLoS ONE. 2020;15:e0229819. doi: 10.1371/journal.pone.0229819. PubMed DOI PMC

Steed P.M., Tansey M.G., Zalevsky J., Zhukovsky E.A., DesJarlais J.R., Szymkowski D.E., Abbott C., Carmichael D., Chan C., Cherry L., et al. Inactivation of TNF Signaling by Rationally Designed Dominant-Negative TNF Variants. Science. 2003;301:1895–1898. doi: 10.1126/science.1081297. PubMed DOI

Cavanagh C., Tse Y.C., Nguyen H.-B., Krantic S., Breitner J.C., Quirion R., Wong T.P. Inhibiting tumor necrosis factor-α before amyloidosis prevents synaptic deficits in an Alzheimer’s disease model. Neurobiol. Aging. 2016;47:41–49. doi: 10.1016/j.neurobiolaging.2016.07.009. PubMed DOI

MacPherson K.P., Sompol P., Kannarkat G.T., Chang J., Sniffen L., Wildner M.E., Norris C.M., Tansey M.G. Peripheral administration of the soluble TNF inhibitor XPro1595 modifies brain immune cell profiles, decreases beta-amyloid plaque load, and rescues impaired long-term potentiation in 5xFAD mice. Neurobiol. Dis. 2017;102:81–95. doi: 10.1016/j.nbd.2017.02.010. PubMed DOI PMC

McAlpine F.E., Lee J.K., Harms A.S., Ruhn K.A., Blurton-Jones M., Hong J., Das P., Golde T.E., LaFerla F.M., Oddo S., et al. Inhibition of soluble TNF signaling in a mouse model of Alzheimer’s disease prevents pre-plaque amyloid-associated neuropathology. Neurobiol. Dis. 2009;34:163–177. doi: 10.1016/j.nbd.2009.01.006. PubMed DOI PMC

Sama D.M., Mohmmad Abdul H., Furman J.L., Artiushin I.A., Szymkowski D.E., Scheff S.W., Norris C.M. Inhibition of soluble tumor necrosis factor ameliorates synaptic alterations and Ca2+ dysregulation in aged rats. PLoS ONE. 2012;7:e38170. doi: 10.1371/journal.pone.0038170. PubMed DOI PMC

Yiannopoulou K.G., Papageorgiou S.G. Current and Future Treatments in Alzheimer Disease: An Update. J. Cent. Nerv. Syst. Dis. 2020;12:1179573520907397. doi: 10.1177/1179573520907397. PubMed DOI PMC

Jung Y.J., Tweedie D., Scerba M.T., Greig N.H. Neuroinflammation as a Factor of Neurodegenerative Disease: Thalidomide Analogs as Treatments. Front. Cell Dev. Biol. 2019;7:313. doi: 10.3389/fcell.2019.00313. PubMed DOI PMC

He P., Cheng X., Staufenbiel M., Li R., Shen Y. Long-Term Treatment of Thalidomide Ameliorates Amyloid-Like Pathology through Inhibition of β-Secretase in a Mouse Model of Alzheimer’s Disease. PLoS ONE. 2013;8:e55091. doi: 10.1371/journal.pone.0055091. PubMed DOI PMC

Decourt B., Wilson J., Ritter A., Dardis C., DiFilippo F.P., Zhuang X., Cordes D., Lee G., Fulkerson N.D., Rose T.S., et al. MCLENA-1: A Phase II Clinical Trial for the Assessment of Safety, Tolerability, and Efficacy of Lenalidomide in Patients with Mild Cognitive Impairment Due to Alzheimer’s Disease. Open Access J. Clin. Trials. 2020;ume 12:1–13. doi: 10.2147/OAJCT.S221914. PubMed DOI PMC

Tweedie D., Ferguson R.A., Fishman K., Frankola K.A., Van Praag H., Holloway H.W., Luo W., Li Y., Caracciolo L., Russo I., et al. Tumor necrosis factor-α synthesis inhibitor 3,6’-dithiothalidomide attenuates markers of inflammation, Alzheimer pathology and behavioral deficits in animal models of neuroinflammation and Alzheimer’s disease. J. Neuroinflamm. 2012;9:1032–1042. doi: 10.1186/1742-2094-9-106. PubMed DOI PMC

Lin C.T., Lecca D., Yang L.Y., Luo W., Scerba M.T., Tweedie D., Huang P.S., Jung Y.J., Kim D.S., Yang C.H., et al. 3,6’-dithiopomalidomide reduces neural loss, inflammation, behavioral deficits in brain injury and microglial activation. Elife. 2020;9:e54726. doi: 10.7554/eLife.54726. PubMed DOI PMC

Russo I., Caracciolo L., Tweedie D., Choi S.-H., Greig N.H., Barlati S., Bosetti F. 3,6′-Dithiothalidomide, a new TNF-α synthesis inhibitor, attenuates the effect of Aβ1-42 intracerebroventricular injection on hippocampal neurogenesis and memory deficit. J. Neurochem. 2012;122:1181–1192. doi: 10.1111/j.1471-4159.2012.07846.x. PubMed DOI PMC

Gabbita S.P., Srivastava M.K., Eslami P., Johnson M.F., Kobritz N.K., Tweedie D., Greig N.H., Zemlan F.P., Sharma S.P., Harris-White M.E. Early intervention with a small molecule inhibitor for tumor necrosis factor-α prevents cognitive deficits in a triple transgenic mouse model of Alzheimer’s disease. J. Neuroinflamm. 2012;9:236. doi: 10.1186/1742-2094-9-99. PubMed DOI PMC

Kirkland J.L., Tchkonia T., Zhu Y., Niedernhofer L.J., Robbins P.D. The Clinical Potential of Senolytic Drugs. J. Am. Geriatr. Soc. 2017;65:2297–2301. doi: 10.1111/jgs.14969. PubMed DOI PMC

Kirkland J.L., Tchkonia T. Cellular senescence: A translational perspective. eBioMedicine. 2017;21:21–28. doi: 10.1016/j.ebiom.2017.04.013. PubMed DOI PMC

Zhu Y., Doornebal E.J., Pirtskhalava T., Giorgadze N., Wentworth M., Fuhrmann-Stroissnigg H., Niedernhofer L.J., Robbins P.D., Tchkonia T., Kirkland J.L. New agents that target senescent cells: The flavone, fisetin, and the BCL-XL inhibitors, A1331852 and A1155463. Aging. 2017;9:955–963. doi: 10.18632/aging.101202. PubMed DOI PMC

Baker D.J., Petersen R.C. Cellular senescence in brain aging and neurodegenerative diseases: Evidence and perspectives. J. Clin. Investig. 2018;128:1208–1216. doi: 10.1172/JCI95145. PubMed DOI PMC

Farr J.N., Fraser D.G., Wang H., Jaehn K., Ogrodnik M.B., Weivoda M.M., Drake M.T., Tchkonia T., Lebrasseur N.K., Kirkland J.L., et al. Identification of Senescent Cells in the Bone Microenvironment. J. Bone Miner. Res. 2016;31:1920–1929. doi: 10.1002/jbmr.2892. PubMed DOI PMC

Jurk D., Wilson C., Passos J.F., Oakley F., Correia-Melo C., Greaves L., Saretzki G., Fox C., Lawless C., Anderson R., et al. Chronic inflammation induces telomere dysfunction and accelerates ageing in mice. Nat. Commun. 2014;5:4172. doi: 10.1038/ncomms5172. PubMed DOI PMC

Sabogal-Guaqueta A.M., Munoz-Manco J.I., Ramirez-Pineda J.R., Lamprea-Rodriguez M., Osorio E., Cardona-Gomez G.P. The flavonoid quercetin ameliorates Alzheimer’s disease pathology and protects cognitive and emotional function in aged triple transgenic Alzheimer’s disease model mice. Neuropharmacology. 2015;93:134–145. doi: 10.1016/j.neuropharm.2015.01.027. PubMed DOI PMC

Kirkland J.L., Tchkonia T. Senolytic drugs: From discovery to translation. J. Intern. Med. 2020;288:518–536. doi: 10.1111/joim.13141. PubMed DOI PMC

Wissler Gerdes E.O., Zhu Y., Weigand B.M., Tripathi U., Burns T.C., Tchkonia T., Kirkland J.L. Cellular senescence in aging and age-related diseases: Implications for neurodegenerative diseases. Int. Rev. Neurobiol. 2020;155:203–234. PubMed PMC

Yousefzadeh M.J., Zhu Y., McGowan S.J., Angelini L., Fuhrmann-Stroissnigg H., Xu M., Ling Y.Y., Melos K.I., Pirtskhalava T., Inman C.L., et al. Fisetin is a senotherapeutic that extends health and lifespan. EBioMedicine. 2018;36:18–28. doi: 10.1016/j.ebiom.2018.09.015. PubMed DOI PMC

Garbarino V.R., Tran S., E Glassman J., Kirkland J.L., Musi N., Seshadri S., E Orr M. A head-to-head comparison between senolytic therapies, dasatinib plus quercetin and fisetin, indicates sex- and genotype-specific differences in translationally relevant outcomes. Alzheimer’s Dement. 2020;16 doi: 10.1002/alz.047607. DOI

Jiang H., Gong T., Zhou R. The strategies of targeting the NLRP3 inflammasome to treat inflammatory diseases. Adv. Immunol. 2020;145:55–93. doi: 10.1016/bs.ai.2019.11.003. PubMed DOI

Chauhan D., Walle L.V., Lamkanfi M. Therapeutic modulation of inflammasome pathways. Immunol. Rev. 2020;297:123–138. doi: 10.1111/imr.12908. PubMed DOI PMC

Zheng D., Liwinski T., Elinav E. Inflammasome activation and regulation: Toward a better understanding of complex mechanisms. Cell Discov. 2020;6:36. doi: 10.1038/s41421-020-0167-x. PubMed DOI PMC

Goldberg E.L., Dixit V.D. Drivers of age-related inflammation and strategies for healthspan extension. Immunol Rev. 2015;265:63–74. doi: 10.1111/imr.12295. PubMed DOI PMC

El-Sharkawy L.Y., Brough D., Freeman S. Inhibiting the NLRP3 Inflammasome. Molecules. 2020;25:5533. doi: 10.3390/molecules25235533. PubMed DOI PMC

Coll R.C., Robertson A.A.B., Chae J.J., Higgins S.C., Muñoz-Planillo R., Inserra M.C., Vetter I., Dungan L.S., Monks B.G., Stutz A., et al. A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases. Nat. Med. 2015;21:248–255. doi: 10.1038/nm.3806. PubMed DOI PMC

Coll R.C., Hill J.R., Day C.J., Zamoshnikova A., Boucher D., Massey N.L., Chitty J.L., Fraser J.A., Jennings M.P., Robertson A.A.B., et al. MCC950 directly targets the NLRP3 ATP-hydrolysis motif for inflammasome inhibition. Nat. Chem. Biol. 2019;15:556–559. doi: 10.1038/s41589-019-0277-7. PubMed DOI

Jiang M., Li R., Lyu J., Li X., Wang W., Wang Z., Sheng H., Zhang W., Karhausen J., Yang W. MCC950, a selective NLPR3 inflammasome inhibitor, improves neurologic function and survival after cardiac arrest and resuscitation. J. Neuroinflamm. 2020;17:256. doi: 10.1186/s12974-020-01933-y. PubMed DOI PMC

Dempsey C., Rubio Araiz A., Bryson K.J., Finucane O., Larkin C., Mills E.L., Robertson A.A., Cooper M.A., O’Neill L.A., Lynch M.A. Inhibiting the NLRP3 inflammasome with MCC950 promotes non-phlogistic clearance of amyloid-β and cognitive function in APP/PS1 mice. Brain Behav. Immun. 2017;61:306–316. doi: 10.1016/j.bbi.2016.12.014. PubMed DOI

Riella L.V., Paterson A.M., Sharpe A.H., Chandraker A. Role of the PD-1 Pathway in the Immune Response. Arab. Archaeol. Epigr. 2012;12:2575–2587. doi: 10.1111/j.1600-6143.2012.04224.x. PubMed DOI PMC

Zhao J., Ji R.-R. Anti-PD-1 treatment as a neurotherapy to enhance neuronal excitability, synaptic plasticity and memory. bioRxiv. 2019;2019 doi: 10.1101/870600. DOI

Laumet G., Ma J., Robison A.J., Kumari S., Heijnen C.J., Kavelaars A. T Cells as an Emerging Target for Chronic Pain Therapy. Front. Mol. Neurosci. 2019;12:216. doi: 10.3389/fnmol.2019.00216. PubMed DOI PMC

Chamoto K., Al-Habsi M., Honjo T. Role of PD-1 in Immunity and Diseases. Curr. Top. Microbiol. Immunol. 2017;410:75–97. doi: 10.1007/82_2017_67. PubMed DOI

Curdy N., Lanvin O., Laurent C., Fournié J.-J., Franchini D.-M. Regulatory Mechanisms of Inhibitory Immune Checkpoint Receptors Expression. Trends Cell Biol. 2019;29:777–790. doi: 10.1016/j.tcb.2019.07.002. PubMed DOI

Baruch K., Rosenzweig N., Kertser A., Deczkowska A., Sharif A.M., Spinrad A., Tsitsou-Kampeli A., Sarel A., Cahalon L., Schwartz M. Breaking immune tolerance by targeting Foxp3+ regulatory T cells mitigates Alzheimer’s disease pathology. Nat. Commun. 2015;6:7967. doi: 10.1038/ncomms8967. PubMed DOI PMC

Santarpia M., González-Cao M., Viteri S., Karachaliou N., Altavilla G., Rosell R. Programmed cell death protein-1/programmed cell death ligand-1 pathway inhibition and predictive biomarkers: Understanding transforming growth factor-beta role. Transl. Lung Cancer Res. 2015;4:728–742. PubMed PMC

Schwartz M., Arad M., Ben-Yehuda H. Potential immunotherapy for Alzheimer disease and age-related dementia. Dialog. Clin. Neurosci. 2019;21:21–25. PubMed PMC

Munafò A., Burgaletto C., Di Benedetto G., Di Mauro M., Di Mauro R., Bernardini R., Cantarella G. Repositioning of Immunomodulators: A Ray of Hope for Alzheimer’s Disease? Front. Neurosci. 2020;14:14. doi: 10.3389/fnins.2020.614643. PubMed DOI PMC

Baruch K., Deczkowska A., Rosenzweig N., Tsitsou-Kampeli A., Sharif A.M., Matcovitch-Natan O., Kertser A., David E., Amit I., Schwartz M. PD-1 immune checkpoint blockade reduces pathology and improves memory in mouse models of Alzheimer’s disease. Nat. Med. 2016;22:135–137. doi: 10.1038/nm.4022. PubMed DOI

Rogers N.K., Romero C., Sanmartín C.D., Ponce D.P., Salech F., López M.N., Gleisner A., Tempio F., Behrens M.I. Inverse Relationship Between Alzheimer’s Disease and Cancer: How Immune Checkpoints Might Explain the Mechanisms Underlying Age-Related Diseases. J. Alzheimer’s Dis. 2020;73:443–454. doi: 10.3233/JAD-190839. PubMed DOI

Rosenzweig N., Dvir-Szternfeld R., Tsitsou-Kampeli A., Keren-Shaul H., Ben-Yehuda H., Weill-Raynal P., Cahalon L., Kertser A., Baruch K., Amit I., et al. PD-1/PD-L1 checkpoint blockade harnesses monocyte-derived macrophages to combat cognitive impairment in a tauopathy mouse model. Nat. Commun. 2019;10:1–15. doi: 10.1038/s41467-019-08352-5. PubMed DOI PMC

Latta-Mahieu M., Elmer B., Bretteville A., Wang Y., Lopez-Grancha M., Goniot P., Moindrot N., Ferrari P., Blanc V., Schussler N., et al. Systemic immune-checkpoint blockade with anti-PD1 antibodies does not alter cerebral amyloid-β burden in several amyloid transgenic mouse models. Glia. 2017;66:492–504. doi: 10.1002/glia.23260. PubMed DOI

Obst J., Mancuso R., Simon E., Gomez-Nicola D. PD-1 deficiency is not sufficient to induce myeloid mobilization to the brain or alter the inflammatory profile during chronic neurodegeneration. Brain Behav. Immun. 2018;73:708–716. doi: 10.1016/j.bbi.2018.08.006. PubMed DOI PMC

Li S., Hayden E.Y., Garcia V.J., Fuchs D.-T., Sheyn J., Daley D.A., Rentsendorj A., Torbati T., Black K.L., Rutishauser U., et al. Activated bone marrow-derived macrophages eradicate Alzheimer’s-related Aβ42 Oligomers and protect synapses. Front. Immunol. 2020;11:49. doi: 10.3389/fimmu.2020.00049. PubMed DOI PMC

van de Donk N.W.C.J. Immunomodulatory effects of CD38-targeting antibodies. Immunol. Lett. 2018;199:16–22. doi: 10.1016/j.imlet.2018.04.005. PubMed DOI

Guerreiro S., Privat A.-L., Bressac L., Toulorge D. CD38 in Neurodegeneration and Neuroinflammation. Cells. 2020;9:471. doi: 10.3390/cells9020471. PubMed DOI PMC

Blacher E., Dadali T., Bespalko A., Msc V.J.H., Grimm M.O.W., Hartmann T., Lund F.E., Stein R., Levy A. Alzheimer’s disease pathology is attenuated in a CD38-deficient mouse model. Ann. Neurol. 2015;78:88–103. doi: 10.1002/ana.24425. PubMed DOI PMC

Zhao L. CD33 in Alzheimer’s Disease—Biology, Pathogenesis, and Therapeutics: A Mini-Review. Gerontology. 2019;65:323–331. doi: 10.1159/000492596. PubMed DOI

Malik M., Simpson J.F., Parikh I., Wilfred B.R., Fardo D.W., Nelson P.T., Estus S. CD33 Alzheimer’s Risk-Altering Polymorphism, CD33 Expression, and Exon 2 Splicing. J. Neurosci. 2013;33:13320–13325. doi: 10.1523/JNEUROSCI.1224-13.2013. PubMed DOI PMC

Griciuc A., Serrano-Pozo A., Parrado A.R., Lesinski A.N., Asselin C.N., Mullin K., Hooli B., Choi S.H., Hyman B.T., Tanzi R.E. Alzheimer’s Disease Risk Gene CD33 Inhibits Microglial Uptake of Amyloid Beta. Neuron. 2013;78:631–643. doi: 10.1016/j.neuron.2013.04.014. PubMed DOI PMC

Miles L.A., Hermans S.J., Crespi G.A., Gooi J.H., Doughty L., Nero T.L., Markulić J., Ebneth A., Wroblowski B., Oehlrich D., et al. Small Molecule Binding to Alzheimer Risk Factor CD33 Promotes Aβ Phagocytosis. iScience. 2019;19:110–118. doi: 10.1016/j.isci.2019.07.023. PubMed DOI PMC

Vom Berg J., Prokop S., Miller K.R., Obst J., Kälin R.E., Lopategui-Cabezas I., Wegner A., Mair F., Schipke C.G., Peters O., et al. Inhibition of IL-12/IL-23 signaling reduces Alzheimer’s disease-like pathology and cognitive decline. Nat. Med. 2012;18:1812–1819. doi: 10.1038/nm.2965. PubMed DOI

Town T., Vendrame M., Patel A., Poetter D., DelleDonne A., Mori T., Smeed R., Crawford F., Klein T., Tan J., et al. Reduced Th1 and enhanced Th2 immunity after immunization with Alzheimer’s beta-amyloid(1-42) J. Neuroimmunol. 2002;132:49–59. doi: 10.1016/S0165-5728(02)00307-7. PubMed DOI

Hu W.T., Holtzman D.M., Fagan A.M., Shaw L.M., Perrin R., Arnold S.E., Grossman M., Xiong C., Craig-Schapiro R., Clark C.M., et al. Plasma multianalyte profiling in mild cognitive impairment and Alzheimer disease. Neurology. 2012;79:897–905. doi: 10.1212/WNL.0b013e318266fa70. PubMed DOI PMC

Teng M.W.L., Bowman E.P., McElwee J.J., Smyth M.J., Casanova J.-L., Cooper A.M., Cua D.J. IL-12 and IL-23 cytokines: From discovery to targeted therapies for immune-mediated inflammatory diseases. Nat. Med. 2015;21:719–729. doi: 10.1038/nm.3895. PubMed DOI

Scott L.J. Glatiramer acetate: A review of its use in patients with relapsing-remitting multiple sclerosis and in delaying the onset of clinically definite multiple sclerosis. CNS Drugs. 2013;27:971–988. doi: 10.1007/s40263-013-0117-3. PubMed DOI

Arnon R., Aharoni R. Glatiramer Acetate: From Bench to Bed and Back. ISR Med. Assoc. J. 2019;21:151–157. PubMed

Chen L., Yao Y., Wei C., Sun Y., Ma X., Zhang R., Xu X., Hao J. T cell immunity to glatiramer acetate ameliorates cognitive deficits induced by chronic cerebral hypoperfusion by modulating the microenvironment. Sci. Rep. 2015;5:14308. doi: 10.1038/srep14308. PubMed DOI PMC

Vieira P.L., Heystek H.C., Wormmeester J., Wierenga E.A., Kapsenberg M.L. Glatiramer Acetate (Copolymer-1, Copaxone) Promotes Th2 Cell Development and Increased IL-10 Production Through Modulation of Dendritic Cells. J. Immunol. 2003;170:4483–4488. doi: 10.4049/jimmunol.170.9.4483. PubMed DOI

Lalive P.H., Neuhaus O., Benkhoucha M., Burger D., Hohlfeld R., Zamvil S.S., Weber M.S. Glatiramer acetate in the treatment of multiple sclerosis: Emerging concepts regarding its mechanism of action. CNS Drugs. 2011;25:401–414. doi: 10.2165/11588120-000000000-00000. PubMed DOI PMC

Koronyo Y., Salumbides B.C., Sheyn J., Pelissier L., Li S., Ljubimov V., Moyseyev M., Daley D., Fuchs D.-T., Pham M., et al. Therapeutic effects of glatiramer acetate and grafted CD115+monocytes in a mouse model of Alzheimer’s disease. Brain. 2015;138:2399–2422. doi: 10.1093/brain/awv150. PubMed DOI PMC

Butovsky O., Koronyo-Hamaoui M., Kunis G., Ophir E., Landa G., Cohen H., Schwartz M. Glatiramer acetate fights against Alzheimer’s disease by inducing dendritic-like microglia expressing insulin-like growth factor 1. Proc. Natl. Acad. Sci. USA. 2006;103:11784–11789. doi: 10.1073/pnas.0604681103. PubMed DOI PMC

Frenkel D., Maron R., Burt D.S., Weiner H.L. Nasal vaccination with a proteosome-based adjuvant and glatiramer acetate clears beta-amyloid in a mouse model of Alzheimer disease. J. Clin. Investig. 2005;115:2423–2433. doi: 10.1172/JCI23241. PubMed DOI PMC

Bakalash S., Pham M., Koronyo Y., Salumbides B.C., Kramerov A., Seidenberg H., Berel D., Black K.L., Koronyo-Hamaoui M. Egr1 Expression Is Induced Following Glatiramer Acetate Immunotherapy in Rodent Models of Glaucoma and Alzheimer’s Disease. Investig. Opthalmology Vis. Sci. 2011;52:9033–9046. doi: 10.1167/iovs.11-7498. PubMed DOI

Khanna A.K. MECHANISM OF THE COMBINATION IMMUNOSUPPRESSIVE EFFECTS OF RAPAMYCIN WITH EITHER CYCLOSPORINE OR TACROLIMUS. Transplantation. 2000;70:690–694. doi: 10.1097/00007890-200008270-00027. PubMed DOI

Lee R.K.K., Knapp S., Wurtman R.J. Prostaglandin E2 Stimulates Amyloid Precursor Protein Gene Expression: Inhibition by Immunosuppressants. J. Neurosci. 1999;19:940–947. doi: 10.1523/JNEUROSCI.19-03-00940.1999. PubMed DOI PMC

Rojanathammanee L., Floden A.M., Manocha G.D., Combs C.K. Attenuation of microglial activation in a mouse model of Alzheimer’s disease via NFAT inhibition. J. Neuroinflamm. 2015;12:42. doi: 10.1186/s12974-015-0255-2. PubMed DOI PMC

Rozkalne A., Hyman B.T., Spires-Jones T.L. Calcineurin inhibition with FK506 ameliorates dendritic spine density deficits in plaque-bearing Alzheimer model mice. Neurobiol. Dis. 2011;41:650–654. doi: 10.1016/j.nbd.2010.11.014. PubMed DOI PMC

Kumar A., Singh N. Calcineurin inhibitors improve memory loss and neuropathological changes in mouse model of dementia. Pharmacol. Biochem. Behav. 2017;153:147–159. doi: 10.1016/j.pbb.2016.12.018. PubMed DOI

Alam J., Blackburn K., Patrick D. Neflamapimod: Clinical Phase 2b-Ready Oral Small Molecule Inhibitor of p38α to Reverse Synaptic Dysfunction in Early Alzheimer’s Disease. J. Prev. Alzheimer's Dis. 2017;4:273–278. PubMed

Alam J.J. Selective Brain-Targeted Antagonism of p38 MAPKα Reduces Hippocampal IL-1β Levels and Improves Morris Water Maze Performance in Aged Rats. J. Alzheimer’s Dis. 2015;48:219–227. doi: 10.3233/JAD-150277. PubMed DOI PMC

Fonseca M.I., Ager R.R., Chu S.-H., Yazan O., Sanderson S.D., LaFerla F.M., Taylor S.M., Woodruff T.M., Tenner A.J. Treatment with a C5aR Antagonist Decreases Pathology and Enhances Behavioral Performance in Murine Models of Alzheimer’s Disease. J. Immunol. 2009;183:1375–1383. doi: 10.4049/jimmunol.0901005. PubMed DOI PMC

Hong S., Beja-Glasser V.F., Nfonoyim B.M., Frouin A., Li S., Ramakrishnan S., Merry K.M., Shi Q., Rosenthal A., Barres B.A., et al. Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science. 2016;352:712–716. doi: 10.1126/science.aad8373. PubMed DOI PMC

Lansita J.A., Mease K.M., Qiu H., Yednock T., Sankaranarayanan S., Kramer S. Nonclinical Development of ANX005: A Humanized Anti-C1q Antibody for Treatment of Autoimmune and Neurodegenerative Diseases. Int. J. Toxicol. 2017;36:449–462. doi: 10.1177/1091581817740873. PubMed DOI

Mathieu M.-C., Sawyer N., Greig G.M., Hamel M., Kargman S., Ducharme Y., Lau C.K., Friesen R.W., O’Neill G.P., Gervais F.G., et al. The C3a receptor antagonist SB 290157 has agonist activity. Immunol. Lett. 2005;100:139–145. doi: 10.1016/j.imlet.2005.03.003. PubMed DOI

Porrini V., Lanzillotta A., Branca C., Benarese M., Parrella E., Lorenzini L., Calza L., Flaibani R., Spano P., Imbimbo B., et al. CHF5074 (CSP-1103) induces microglia alternative activation in plaque-free Tg2576 mice and primary glial cultures exposed to beta-amyloid. Neuroscience. 2015;302:112–120. doi: 10.1016/j.neuroscience.2014.10.029. PubMed DOI

Hwangbo D.-S., Lee H.-Y., Abozaid L.S., Min K.-J. Mechanisms of Lifespan Regulation by Calorie Restriction and Intermittent Fasting in Model Organisms. Nutrients. 2020;12:1194. doi: 10.3390/nu12041194. PubMed DOI PMC

Dorling J.L., Martin C.K., Redman L.M. Calorie restriction for enhanced longevity: The role of novel dietary strategies in the present obesogenic environment. Ageing Res. Rev. 2020;64:101038. doi: 10.1016/j.arr.2020.101038. PubMed DOI PMC

Chung H.Y., Kim H.J., Kim J.W., Yu B.P. The inflammation hypothesis of aging: Molecular modulation by calorie restriction. Ann. N. Y. Acad. Sci. 2001;928:327–335. doi: 10.1111/j.1749-6632.2001.tb05662.x. PubMed DOI

Di Francesco A., Di Germanio C., Bernier M., de Cabo R. A time to fast. Science. 2018;362:770–775. doi: 10.1126/science.aau2095. PubMed DOI PMC

Wang Y.-W., He S.-J., Feng X., Cheng J., Luo Y.-T., Tian L., Huang Q. Metformin: A review of its potential indications. Drug Des. Dev. Ther. 2017;ume 11:2421–2429. doi: 10.2147/DDDT.S141675. PubMed DOI PMC

Vieira R., Souto S.B., Sánchez-López E., Machado A.L., Severino P., Jose S., Santini A., Fortuna A., García M.L., Silva A.M. Sugar-Lowering Drugs for Type 2 Diabetes Mellitus and Metabolic Syndrome—Review of Classical and New Compounds: Part-I. Pharmaceuticals. 2019;12:152. doi: 10.3390/ph12040152. PubMed DOI PMC

Partridge L., Piper M.D., Mair W. Dietary restriction in Drosophila. Mech. Ageing Dev. 2005;126:938–950. doi: 10.1016/j.mad.2005.03.023. PubMed DOI

Masoro E.J. Caloric restriction and aging: An update. Exp. Gerontol. 2000;35:299–305. doi: 10.1016/S0531-5565(00)00084-X. PubMed DOI

Onken B., Driscoll M. Metformin induces a dietary restriction-like state and the oxidative stress response to extend C. elegans Healthspan via AMPK, LKB1, and SKN-1. PLoS ONE. 2010;5:e8758. doi: 10.1371/journal.pone.0008758. PubMed DOI PMC

Bharath L.P., Agrawal M., McCambridge G., Nicholas D.A., Hasturk H., Liu J., Jiang K., Liu R., Guo Z., Deeney J., et al. Metformin Enhances Autophagy and Normalizes Mitochondrial Function to Alleviate Aging-Associated Inflammation. Cell Metab. 2020;32:44–55.e6. doi: 10.1016/j.cmet.2020.04.015. PubMed DOI PMC

Kang E.B., Koo J.H., Jang Y.C., Yang C.H., Lee Y., Cosio-Lima L.M., Cho J.Y. Neuroprotective Effects of Endurance Exercise Against High-Fat Diet-Induced Hippocampal Neuroinflammation. J. Neuroendocrinol. 2016;28 doi: 10.1111/jne.12385. PubMed DOI

Park J., Cheon W., Kim K. Effects of Long-Term Endurance Exercise and Lithium Treatment on Neuroprotective Factors in Hippocampus of Obese Rats. Int. J. Environ. Res. Public Heal. 2020;17:3317. doi: 10.3390/ijerph17093317. PubMed DOI PMC

Onyango I.G., Lu J., Rodova M., Lezi E., Crafter A.B., Swerdlow R.H. Regulation of neuron mitochondrial biogenesis and relevance to brain health. Biochim. Biophys. Acta (BBA) Mol. Basis Dis. 2010;1802:228–234. doi: 10.1016/j.bbadis.2009.07.014. PubMed DOI

Radak Z., Suzuki K., Higuchi M., Balogh L., Boldogh I., Koltai E. Physical exercise, reactive oxygen species and neuroprotection. Free Radic. Biol. Med. 2016;98:187–196. doi: 10.1016/j.freeradbiomed.2016.01.024. PubMed DOI

Intlekofer K.A., Cotman C.W. Exercise counteracts declining hippocampal function in aging and Alzheimer’s disease. Neurobiol. Dis. 2013;57:47–55. doi: 10.1016/j.nbd.2012.06.011. PubMed DOI

Dalle S., Rossmeislova L., Koppo K. The Role of Inflammation in Age-Related Sarcopenia. Front. Physiol. 2017;8:1045. doi: 10.3389/fphys.2017.01045. PubMed DOI PMC

Nilsson M.I., Bourgeois J.M., Nederveen J.P., Leite M.R., Hettinga B.P., Bujak A.L., May L., Lin E., Crozier M., Rusiecki D.R., et al. Lifelong aerobic exercise protects against inflammaging and cancer. PLoS ONE. 2019;14:e0210863. doi: 10.1371/journal.pone.0210863. PubMed DOI PMC

Hardeland R. Melatonin and inflammation-Story of a double-edged blade. J. Pineal Res. 2018;65:e12525. doi: 10.1111/jpi.12525. PubMed DOI

Hardeland R. Aging, Melatonin, and the Pro- and Anti-Inflammatory Networks. Int. J. Mol. Sci. 2019;20:1223. doi: 10.3390/ijms20051223. PubMed DOI PMC

Marchal J., Pifferi F., Aujard F. Resveratrol in mammals: Effects on aging biomarkers, age-related diseases, and life span. Ann. N. Y. Acad. Sci. 2013;1290:67–73. doi: 10.1111/nyas.12214. PubMed DOI

Alcaín F.J., Villalba J.M. Sirtuin activators. Expert. Opin. Ther. Pat. 2009;19:403–414. doi: 10.1517/13543770902762893. PubMed DOI

Zhu X., Liu Q., Wang M., Liang M., Yang X., Xu X., Zou H., Qiu J. Activation of Sirt1 by Resveratrol Inhibits TNF-α Induced Inflammation in Fibroblasts. PLoS ONE. 2011;6:e27081. doi: 10.1371/journal.pone.0027081. PubMed DOI PMC

Arbo B.D., André-Miral C., Nasre-Nasser R.G., Schimith L.E., Santos M.G., Costa-Silva D., Muccillo-Baisch A.L., Hort M.A. Resveratrol Derivatives as Potential Treatments for Alzheimer’s and Parkinson’s Disease. Front. Aging Neurosci. 2020;12:103. doi: 10.3389/fnagi.2020.00103. PubMed DOI PMC

Moussa C., Hebron M., Huang X., Ahn J., Rissman R.A., Aisen P.S., Turner R.S. Resveratrol regulates neuro-inflammation and induces adaptive immunity in Alzheimer’s disease. J. Neuroinflamm. 2017;14:1–10. doi: 10.1186/s12974-016-0779-0. PubMed DOI PMC

Turner R.S., Thomas R.G., Craft S., Van Dyck C.H., Mintzer J., Reynolds B.A., Brewer J.B., Rissman R.A., Raman R., Aisen P.S., et al. A randomized, double-blind, placebo-controlled trial of resveratrol for Alzheimer disease. Neurology. 2015;85:1383–1391. doi: 10.1212/WNL.0000000000002035. PubMed DOI PMC

Witte A.V., Kerti L., Margulies D.S., Flöel A. Effects of resveratrol on memory performance, hippocampal functional connectivity, and glucose metabolism in healthy older adults. J. Neurosci. 2014;34:7862–7870. doi: 10.1523/JNEUROSCI.0385-14.2014. PubMed DOI PMC

Jiao F., Gong Z. The Beneficial Roles of SIRT1 in Neuroinflammation-Related Diseases. Oxid. Med. Cell Longev. 2020;2020:6782872. doi: 10.1155/2020/6782872. PubMed DOI PMC

Cannizzo E.S., Clement C.C., Sahu R., Follo C., Santambrogio L. Oxidative stress, inflamm-aging and immunosenescence. J. Proteom. 2011;74:2313–2323. doi: 10.1016/j.jprot.2011.06.005. PubMed DOI

Bachmann M.C., Bellalta S., Basoalto R., Gómez-Valenzuela F., Jalil Y., Lépez M., Matamoros A., Von Bernhardi R. The Challenge by Multiple Environmental and Biological Factors Induce Inflammation in Aging: Their Role in the Promotion of Chronic Disease. Front. Immunol. 2020;11:570083. doi: 10.3389/fimmu.2020.570083. PubMed DOI PMC

Chelombitko M.A. Role of Reactive Oxygen Species in Inflammation: A Minireview. Mosc. Univ. Biol. Sci. Bull. 2018;73:199–202. doi: 10.3103/S009639251804003X. DOI

Jiang Q., Yin J., Chen J., Ma X., Wu M., Liu G., Yao K., Tan B., Yin Y. Mitochondria-Targeted Antioxidants: A Step towards Disease Treatment. Oxidative Med. Cell. Longev. 2020;2020:1–18. doi: 10.1155/2020/8837893. PubMed DOI PMC

Fujimoto C., Yamasoba T. Mitochondria-Targeted Antioxidants for Treatment of Hearing Loss: A Systematic Review. Antioxidants. 2019;8:109. doi: 10.3390/antiox8040109. PubMed DOI PMC

Oyewole A.O., Birch-Machin M.A. Mitochondria-targeted antioxidants. FASEB J. 2015;29:4766–4771. doi: 10.1096/fj.15-275404. PubMed DOI

Fang Y., Hu X.H., Jia Z.G., Xu M.H., Guo Z.Y., Gao F.H. Tiron protects against UVB-induced senescence-like characteristics in human dermal fibroblasts by the inhibition of superoxide anion production and glutathione depletion. Australas. J. Dermatol. 2012;53:172–180. doi: 10.1111/j.1440-0960.2012.00912.x. PubMed DOI

For The Carmis Study Group. Piermarocchi S., Saviano S., Parisi V., Tedeschi M., Panozzo G., Scarpa G., Boschi G., Giudice G.L., Sartore M., et al. Carotenoids in Age-Related Maculopathy Italian Study (CARMIS): Two-Year Results of a Randomized Study. Eur. J. Ophthalmol. 2012;22:216–225. doi: 10.5301/ejo.5000069. PubMed DOI

Wu W., Wang X., Xiang Q., Meng X., Peng Y., Du N., Liu Z., Sun Q., Wang C., Liu X. Astaxanthin alleviates brain aging in rats by attenuating oxidative stress and increasing BDNF levels. Food Funct. 2013;5:158–166. doi: 10.1039/C3FO60400D. PubMed DOI

Gill H.S., Rutherfurd K.J., Cross M.L., Gopal P.K. Enhancement of immunity in the elderly by dietary supplementation with the probiotic Bifidobacterium lactis HN019. Am. J. Clin. Nutr. 2001;74:833–839. doi: 10.1093/ajcn/74.6.833. PubMed DOI

Dong H., Rowland I., Thomas L.V., Yaqoob P. Immunomodulatory effects of a probiotic drink containing Lactobacillus casei Shirota in healthy older volunteers. Eur. J. Nutr. 2013;52:1853–1863. doi: 10.1007/s00394-012-0487-1. PubMed DOI

Vulevic J., Drakoularakou A., Yaqoob P., Tzortzis G., Gibson G.R. Modulation of the fecal microflora profile and immune function by a novel trans-galactooligosaccharide mixture (B-GOS) in healthy elderly volunteers. Am. J. Clin. Nutr. 2008;88:1438–1446. PubMed

Frasca D., Blomberg B.B. Inflammaging decreases adaptive and innate immune responses in mice and humans. Biogerontology. 2016;17:7–19. doi: 10.1007/s10522-015-9578-8. PubMed DOI PMC

Man A.W.C., Zhou Y., Xia N., Li H. Involvement of Gut Microbiota, Microbial Metabolites and Interaction with Polyphenol in Host Immunometabolism. Nutrients. 2020;12:3054. doi: 10.3390/nu12103054. PubMed DOI PMC

Angelucci F., Cechova K., Amlerova J., Hort J. Antibiotics, gut microbiota, and Alzheimer’s disease. J. Neuroinflamm. 2019;16:1–10. doi: 10.1186/s12974-019-1494-4. PubMed DOI PMC

He Y., Li B., Sun D., Chen S. Gut Microbiota: Implications in Alzheimer’s Disease. J. Clin. Med. 2020;9:2042. doi: 10.3390/jcm9072042. PubMed DOI PMC

Haran J.P., Bhattarai S.K., Foley S.E., Dutta P., Ward D.V., Bucci V., McCormick B.A. Alzheimer’s Disease Microbiome Is Associated with Dysregulation of the Anti-Inflammatory P-Glycoprotein Pathway. mBio. 2019;10:e00632-19. doi: 10.1128/mBio.00632-19. PubMed DOI PMC

Zhu F., Li C., Chu F., Tian X., Zhu J. Target Dysbiosis of Gut Microbes as a Future Therapeutic Manipulation in Alzheimer’s Disease. Front. Aging Neurosci. 2020;12:544235. doi: 10.3389/fnagi.2020.544235. PubMed DOI PMC

Sharma R., Padwad Y. Probiotic bacteria as modulators of cellular senescence: Emerging concepts and opportunities. Gut Microbes. 2020;11:335–349. doi: 10.1080/19490976.2019.1697148. PubMed DOI PMC

Shabbir U., Arshad M., Sameen A., Oh D.-H. Crosstalk between Gut and Brain in Alzheimer’s Disease: The Role of Gut Microbiota Modulation Strategies. Nutrients. 2021;13:690. doi: 10.3390/nu13020690. PubMed DOI PMC

Kesika P., Suganthy N., Sivamaruthi B.S., Chaiyasut C. Role of gut-brain axis, gut microbial composition, and probiotic intervention in Alzheimer’s disease. Life Sci. 2021;264:118627. doi: 10.1016/j.lfs.2020.118627. PubMed DOI

Bonfili L., Cecarini V., Gogoi O., Gong C., Cuccioloni M., Angeletti M., Rossi G., Eleuteri A.M. Microbiota modulation as preventative and therapeutic approach in Alzheimer’s disease. FEBS J. 2020 doi: 10.1111/febs.15571. PubMed DOI

Liu S., Gao J., Zhu M., Liu K., Zhang H.-L. Gut Microbiota and Dysbiosis in Alzheimer’s Disease: Implications for Pathogenesis and Treatment. Mol. Neurobiol. 2020;57:5026–5043. doi: 10.1007/s12035-020-02073-3. PubMed DOI PMC

Portis S.M., Chaput D., Burroughs B., Hudson C., Sanberg P.R., Bickford P.C. Effects of nutraceutical intervention on serum proteins in aged rats. GeroScience. 2020;42:703–713. doi: 10.1007/s11357-020-00174-4. PubMed DOI PMC

Sadhukhan P., Saha S., Dutta S., Mahalanobish S., Sil P.C. Nutraceuticals: An emerging therapeutic approach against the pathogenesis of Alzheimer’s disease. Pharmacol. Res. 2018;129:100–114. doi: 10.1016/j.phrs.2017.11.028. PubMed DOI

Calfio C., Gonzalez A., Singh S.K., Rojo L.E., Maccioni R.B. The Emerging Role of Nutraceuticals and Phytochemicals in the Prevention and Treatment of Alzheimer’s Disease. J. Alzheimer’s Dis. 2020;77:33–51. doi: 10.3233/JAD-200443. PubMed DOI

Vaiserman A., Koliada A., Lushchak O. Neuroinflammation in pathogenesis of Alzheimer’s disease: Phytochemicals as potential therapeutics. Mech. Ageing Dev. 2020;189:111259. doi: 10.1016/j.mad.2020.111259. PubMed DOI

Flowers A., Lee J.-Y., Acosta S., Hudson C., Small B., Sanberg C.D., Bickford P.C., Grimmig B. NT-020 treatment reduces inflammation and augments Nrf-2 and Wnt signaling in aged rats. J. Neuroinflamm. 2015;12:174. doi: 10.1186/s12974-015-0395-4. PubMed DOI PMC

Alpert P.T. The Role of Vitamins and Minerals on the Immune System. Home Heal. Care Manag. Pr. 2017;29:199–202. doi: 10.1177/1084822317713300. DOI

Mora J.R., Iwata M., von Andrian U.H. Vitamin effects on the immune system: Vitamins A and D take centre stage. Nat. Rev. Immunol. 2008;8:685–698. doi: 10.1038/nri2378. PubMed DOI PMC

Maggini S., Pierre A., Calder P.C. Immune Function and Micronutrient Requirements Change over the Life Course. Nutrients. 2018;10:491 PubMed PMC

Abiri B., Vafa M. Micronutrients that Affect Immunosenescence. Adv. Exp. Med. Biol. 2020;1260:13–31. PubMed

Meydani S.N., Meydani M., Blumberg J.B., Leka L.S., Siber G., Loszewski R., Thompson C., Pedrosa M.C., Diamond R.D., Stollar B.D. Vitamin E supplementation and in vivo immune response in healthy elderly subjects. A randomized controlled trial. JAMA. 1997;277:1380–1386. doi: 10.1001/jama.1997.03540410058031. PubMed DOI

De la Fuente M., Hernanz A., Guayerbas N., Victor V.M., Arnalich F. Vitamin E ingestion improves several immune functions in elderly men and women. Free Radic Res. 2008;42:272–280. doi: 10.1080/10715760801898838. PubMed DOI

Pallast E.G., Schouten E.G., De Waart F.G., Fonk H.C., Doekes G., Von Blomberg B.M., Kok F.J. Effect of 50- and 100-mg vitamin E supplements on cellular immune function in noninstitutionalized elderly persons. Am. J. Clin. Nutr. 1999;69:1273–1281. doi: 10.1093/ajcn/69.6.1273. PubMed DOI

Tan B.L., Norhaizan M.E., Liew W.-P.-P., Rahman H.S. Antioxidant and Oxidative Stress: A Mutual Interplay in Age-Related Diseases. Front. Pharmacol. 2018;9:1162. doi: 10.3389/fphar.2018.01162. PubMed DOI PMC

Tan B.L., Norhaizan M.E. Carotenoids: How Effective Are They to Prevent Age-Related Diseases? Molecules. 2019;24:1801. doi: 10.3390/molecules24091801. PubMed DOI PMC

Monacelli F., Acquarone E., Giannotti C., Borghi R., Nencioni A. Vitamin C, Aging and Alzheimer’s Disease. Nutrients. 2017;9:670. doi: 10.3390/nu9070670. PubMed DOI PMC

Maggini S., Wintergerst E.S., Beveridge S., Hornig D.H. Selected vitamins and trace elements support immune function by strengthening epithelial barriers and cellular and humoral immune responses. Br. J. Nutr. 2007;98:S29–S35. doi: 10.1017/S0007114507832971. PubMed DOI

Zhitkovich A. Nuclear and Cytoplasmic Functions of Vitamin C. Chem. Res. Toxicol. 2020;33:2515–2526. doi: 10.1021/acs.chemrestox.0c00348. PubMed DOI PMC

Hemilae H. Vitamin C and infections. Nutrients. 2017;9:339. doi: 10.3390/nu9040339. PubMed DOI PMC

Carr A.C., Maggini S. Vitamin C and Immune Function. Nutrients. 2017;9:1211. doi: 10.3390/nu9111211. PubMed DOI PMC

Tanaka M., Muto N., Gohda E., Yamamoto I. Enhancement by Ascorbic Acid 2-Glucoside or Repeated Additions of Ascorbate of Mitogen-Induced IgM and IgG Productions by Human Peripheral Blood Lymphocytes. Jpn. J. Pharmacol. 1994;66:451–456. doi: 10.1254/jjp.66.451. PubMed DOI

Cabrera Á.J.R. Zinc, aging, and immunosenescence: An overview. Pathobiol. Aging Age-Related Dis. 2015;5:25592. doi: 10.3402/pba.v5.25592. PubMed DOI PMC

Jarosz M., Olbert M., Wyszogrodzka G., Młyniec K., Librowski T. Antioxidant and anti-inflammatory effects of zinc. Zinc-dependent NF-κB signaling. Inflammopharmacology. 2017;25:11–24. doi: 10.1007/s10787-017-0309-4. PubMed DOI PMC

Wong C.P., Ho E. Zinc and its role in age-related inflammation and immune dysfunction. Mol. Nutr. Food Res. 2012;56:77–87. doi: 10.1002/mnfr.201100511. PubMed DOI

Prasad A.S. Clinical, immunological, anti-inflammatory and antioxidant roles of zinc. Exp. Gerontol. 2008;43:370–377. doi: 10.1016/j.exger.2007.10.013. PubMed DOI

Fortes C., Forastiere F., Agabiti N., Fano V., Pacifici R., Virgili F., Piras G., Guidi L., Bartoloni C., Tricerri A., et al. The Effect of Zinc and Vitamin A Supplementation on Immune Response in an Older Population. J. Am. Geriatr. Soc. 1998;46:19–26. doi: 10.1111/j.1532-5415.1998.tb01008.x. PubMed DOI

Lee S.R. Critical role of zinc as either an antioxidant or a prooxidant in cellular systems. Oxid. Med. Cell Longev. 2018;2018:9156285. doi: 10.1155/2018/9156285. PubMed DOI PMC

Pecora F., Persico F., Argentiero A., Neglia C., Esposito S. The Role of Micronutrients in Support of the Immune Response against Viral Infections. Nutrients. 2020;12:3198. doi: 10.3390/nu12103198. PubMed DOI PMC

Prasad A.S., Bao B., Beck F.W., Kucuk O., Sarkar F.H. Antioxidant effect of zinc in humans. Free. Radic. Biol. Med. 2004;37:1182–1190. doi: 10.1016/j.freeradbiomed.2004.07.007. PubMed DOI

Xia S., Shen Y., Yu W. Study on mechanism and intervention of inflamm-aging in rats. Chin. J. Gerontol. 2009;29:2595–2598.

Xia S., Shen Y., Yu W. Inflamm-aging related genes expression in aged rat hippocampus and Icariin intervention outcome. Geriatr. Health Care. 2008;14:340–344.

Zheng J., Hu S., Wang J., Zhang X., Yuan D., Zhang C., Liu C., Wang T., Zhou Z. Icariin improves brain function decline in aging rats by enhancing neuronal autophagy through the AMPK/mTOR/ULK1 pathway. Pharm. Biol. 2021;59:183–191. doi: 10.1080/13880209.2021.1878238. PubMed DOI PMC

Li W.-X., Deng Y.-Y., Li F., Liu B., Liu H.-Y., Shi J.-S., Gong Q.-H. Icariin, a major constituent of flavonoids from Epimedium brevicornum, protects against cognitive deficits induced by chronic brain hypoperfusion via its anti-amyloidogenic effect in rats. Pharmacol. Biochem. Behav. 2015;138:40–48. doi: 10.1016/j.pbb.2015.09.001. PubMed DOI

Yan N., Wen D.S., Zhao Y.R., Xu S.J. Epimedium sagittatum inhibits TLR4/MD-2 mediated NF-κB signaling pathway with anti-inflammatory activity. BMC Complement. Altern. Med. 2018;18:303. doi: 10.1186/s12906-018-2363-x. PubMed DOI PMC

Han G., Zhang C., Qian C., Na M., Ding Y., Zhao H. Total Flavonoids of Epimedium Reduce Inflammatory Reaction via AMPK/SIRT1/NFκB Signaling Pathway in Testes of Natural Aging Rats. Nat. Prod. Res. Dev. 2018;30:1489–1493.

Najít záznam

Citační ukazatele

Nahrávání dat ...

    Možnosti archivace