Aging and age-related neurodegenerative disorders are characterized by the dysfunction or loss of brain nicotinic acetylcholine receptors (nAChRs), and these changes may be related to other senescence markers, such as oxidative stress and DNA repair dysfunction. However, the mechanism of nAChR loss in the aging brain and the modification of this process by drugs (e.g., memantine, Mem) are not yet fully understood. To study whether the differences in nAChR expression in the rat brain occur due to aging or oxidative stress and are modulated by Mem, we analyzed nAChR subunits (at RNA and protein levels) and other biomarkers by real-time quantitative polymerase chain reaction (RQ-PCR) and Western blot validation. Twenty-one female Wistar rats were divided into four groups, depending on age, and the oldest group received injections of Mem or water with the use of intragastric catheters. We studied the cerebral grey matter (CGM), subcortical white matter (SCWM), and cerebellum (Ce). Results showed an age-related decrease of α7 nAChR mRNA level in SCWM. The α7 nAChR mRNA loss was accompanied by reduced expression of 8-oxoguanine DNA glycosylase 1 (OGG1) and an increased tumor necrosis factor alpha (TNFα) level. In the water group, we observed a higher level of α7 nAChR protein in the SCWM and Ce. Biomarker levels changed, but to a different extent depending on the brain area. Importantly, the dysfunction in antioxidative status was stopped and even regressed under Mem treatment. After two weeks of treatment, an increase in TP53 protein level and a decrease in 8-oxo-2'deoxyguanosine (8-oxo-2'dG) level were observed. We conclude that Mem administration may be protective against the senescence process by antioxidative mechanisms.

Center of Assisted Reproduction Department of Obstetrics and Gynecology University Hospital and Masaryk University 625 00 Brno Czech Republic

Department of Biochemistry and Molecular Biology Poznan University of Medical Sciences 6 Świecickiego St 60 781 Poznan Poland

Department of Human Morphology and Embryology Division of Anatomy Wrocław Medical University 50 368 Wroclaw Poland

Department of Physiology Poznan University of Medical Sciences 6 Świecickiego St 60 781 Poznan Poland

Faculty of Medicine Poznan Medical University 55 Bulgarska St 60 320 Poznan Poland

Institute of Veterinary Medicine Nicolaus Copernicus University 87 100 Torun Poland

Laboratory of Neurobiology Department of Neurology Poznan University of Medical Sciences 49 Przybyszewskiego St 60 355 Poznan Poland

Physiology Graduate Faculty North Carolina State University Raleigh NC 27695 USA

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Mohamed W.M.Y., Yi C., Soreq L., Yamashita T. Editorial: Genes and Aging: From Bench-to-Bedside. Front. Aging Neurosci. 2022;14:886967. doi: 10.3389/fnagi.2022.886967. PubMed DOI PMC

Dorszewska J., Ong K.T., Zabel M., Marchetti C. Editorial: Insights into Mechanisms Underlying Brain Impairment in Aging, Volume II. Front. Aging Neurosci. 2023;15:1242271. doi: 10.3389/fnagi.2023.1242271. PubMed DOI PMC

Dorszewska J. Cell Biology of Normal Brain Aging: Synaptic Plasticity-Cell Death. Aging Clin. Exp. Res. 2013;25:25–34. doi: 10.1007/s40520-013-0004-2. PubMed DOI

Kowalska M., Wize K., Prendecki M., Lianeri M., Kozubski W., Dorszewska J. Genetic Variants and Oxidative Stress in Alzheimer’s Disease. Curr. Alzheimer Res. 2020;17:208–223. doi: 10.2174/1567205017666200224121447. PubMed DOI

MohanKumar S.M.J., Murugan A., Palaniyappan A., MohanKumar P.S. Role of Cytokines and Reactive Oxygen Species in Brain Aging. Mech. Ageing Dev. 2023;214:111855. doi: 10.1016/j.mad.2023.111855. PubMed DOI PMC

Iskusnykh I.Y., Zakharova A.A., Kryl’skii E.D., Popova T.N. Aging, Neurodegenerative Disorders, and Cerebellum. Int. J. Mol. Sci. 2024;25:1018. doi: 10.3390/ijms25021018. PubMed DOI PMC

Burmistrov D.E., Gudkov S.V., Franceschi C., Vedunova M.V. Sex as a Determinant of Age-Related Changes in the Brain. Int. J. Mol. Sci. 2024;25:7122. doi: 10.3390/ijms25137122. PubMed DOI PMC

Bychkov M.L., Isaev A.B., Andreev-Andrievskiy A.A., Petrov K., Paramonov A.S., Kirpichnikov M.P., Lyukmanova E.N. Aβ1-42 Accumulation Accompanies Changed Expression of Ly6/uPAR Proteins, Dysregulation of the Cholinergic System, and Degeneration of Astrocytes in the Cerebellum of Mouse Model of Early Alzheimer Disease. Int. J. Mol. Sci. 2023;24:14852. doi: 10.3390/ijms241914852. PubMed DOI PMC

Liu R.-M. Aging, Cellular Senescence, and Alzheimer’s Disease. Int. J. Mol. Sci. 2022;23:1989. doi: 10.3390/ijms23041989. PubMed DOI PMC

Gasiorowska A., Wydrych M., Drapich P., Zadrozny M., Steczkowska M., Niewiadomski W., Niewiadomska G. The Biology and Pathobiology of Glutamatergic, Cholinergic, and Dopaminergic Signaling in the Aging Brain. Front. Aging Neurosci. 2021;13:654931. doi: 10.3389/fnagi.2021.654931. PubMed DOI PMC

Kunnath A.J., Gifford R.H., Wallace M.T. Cholinergic Modulation of Sensory Perception and Plasticity. Neurosci. Biobehav. Rev. 2023;152:105323. doi: 10.1016/j.neubiorev.2023.105323. PubMed DOI PMC

Echeverria V., Mendoza C., Iarkov A. Nicotinic Acetylcholine Receptors and Learning and Memory Deficits in Neuroinflammatory Diseases. Front. Neurosci. 2023;17:1179611. doi: 10.3389/fnins.2023.1179611. PubMed DOI PMC

Lee C.-H., Hung S.-Y. Physiologic Functions and Therapeutic Applications of A7 Nicotinic Acetylcholine Receptor in Brain Disorders. Pharmaceutics. 2022;15:31. doi: 10.3390/pharmaceutics15010031. PubMed DOI PMC

Utkin Y.N. Aging Affects Nicotinic Acetylcholine Receptors in Brain. Cent. Nerv. Syst. Agents Med. Chem. 2019;19:119–124. doi: 10.2174/1871524919666190320102834. PubMed DOI

Crestini A., Carbone E., Rivabene R., Ancidoni A., Rosa P., Tata A.M., Fabrizi E., Locuratolo N., Vanacore N., Lacorte E., et al. A Systematic Review on Drugs Acting as Nicotinic Acetylcholine Receptor Agonists in the Treatment of Dementia. Cells. 2024;13:237. doi: 10.3390/cells13030237. PubMed DOI PMC

Korczowska-Łącka I., Hurła M., Banaszek N., Kobylarek D., Szymanowicz O., Kozubski W., Dorszewska J. Selected Biomarkers of Oxidative Stress and Energy Metabolism Disorders in Neurological Diseases. Mol. Neurobiol. 2023;60:4132–4149. doi: 10.1007/s12035-023-03329-4. PubMed DOI PMC

Ionescu-Tucker A., Cotman C.W. Emerging Roles of Oxidative Stress in Brain Aging and Alzheimer’s Disease. Neurobiol. Aging. 2021;107:86–95. doi: 10.1016/j.neurobiolaging.2021.07.014. PubMed DOI

Mecocci P., Boccardi V., Cecchetti R., Bastiani P., Scamosci M., Ruggiero C., Baroni M. A Long Journey into Aging, Brain Aging, and Alzheimer’s Disease Following the Oxidative Stress Tracks. J. Alzheimers Dis. 2018;62:1319–1335. doi: 10.3233/JAD-170732. PubMed DOI PMC

Kandlur A., Satyamoorthy K., Gangadharan G. Oxidative Stress in Cognitive and Epigenetic Aging: A Retrospective Glance. Front. Mol. Neurosci. 2020;13:41. doi: 10.3389/fnmol.2020.00041. PubMed DOI PMC

Li J., Haj Ebrahimi A., Ali A.B. Advances in Therapeutics to Alleviate Cognitive Decline and Neuropsychiatric Symptoms of Alzheimer’s Disease. Int. J. Mol. Sci. 2024;25:5169. doi: 10.3390/ijms25105169. PubMed DOI PMC

Arleo A., Bareš M., Bernard J.A., Bogoian H.R., Bruchhage M.M.K., Bryant P., Carlson E.S., Chan C.C.H., Chen L.-K., Chung C.-P., et al. Consensus Paper: Cerebellum and Ageing. Cerebellum. 2024;23:802–832. doi: 10.1007/s12311-023-01577-7. PubMed DOI PMC

Cohen J., Mathew A., Dourvetakis K.D., Sanchez-Guerrero E., Pangeni R.P., Gurusamy N., Aenlle K.K., Ravindran G., Twahir A., Isler D., et al. Recent Research Trends in Neuroinflammatory and Neurodegenerative Disorders. Cells. 2024;13:511. doi: 10.3390/cells13060511. PubMed DOI PMC

Aye S., Bouteloup V., Tate A., Wimo A., Handels R., Jean D., Winblad B., Jönsson L. Health-Related Quality of Life in Subjective Cognitive Decline and Mild Cognitive Impairment: A Longitudinal Cohort Analysis. Alzheimers Res. Ther. 2023;15:200. doi: 10.1186/s13195-023-01344-0. PubMed DOI PMC

Mank A., Rijnhart J.J.M., van Maurik I.S., Jönsson L., Handels R., Bakker E.D., Teunissen C.E., van Berckel B.N.M., van Harten A.C., Berkhof J., et al. A Longitudinal Study on Quality of Life Along the Spectrum of Alzheimer’s Disease. Alzheimers Res. Ther. 2022;14:132. doi: 10.1186/s13195-022-01075-8. PubMed DOI PMC

Martyr A., Gamble L.D., Hunt A., Quinn C., Morris R.G., Henderson C., Allan L., Opdebeeck C., Charlwood C., Jones R.W., et al. Differences in Trajectories of Quality of Life According to Type of Dementia: 6-Year Longitudinal Findings from the IDEAL Programme. BMC Med. 2024;22:265. doi: 10.1186/s12916-024-03492-y. PubMed DOI PMC

Gao Y., Zhao Y., Li M., Lawless R.D., Schilling K.G., Xu L., Shafer A.T., Beason-Held L.L., Resnick S.M., Rogers B.P., et al. Functional Alterations in Bipartite Network of White and Grey Matters During Aging. Neuroimage. 2023;278:120277. doi: 10.1016/j.neuroimage.2023.120277. PubMed DOI PMC

Xu L., Gao Y., Li M., Lawless R., Zhao Y., Schilling K.G., Rogers B.P., Anderson A.W., Ding Z., Landman B.A., et al. Functional Correlation Tensors in Brain White Matter and the Effects of Normal Aging. Brain Imaging Behav. 2024;18:1197–1214. doi: 10.1007/s11682-024-00914-6. PubMed DOI PMC

Rozycka A., Steinborn B., Trzeciak W.H. The 1674+11C>T Polymorphism of CHRNA4 Is Associated with Juvenile Myoclonic Epilepsy. Seizure. 2009;18:601–603. doi: 10.1016/j.seizure.2009.06.007. PubMed DOI

Pastor V., Medina J.H. A7 Nicotinic Acetylcholine Receptor in Memory Processing. Eur. J. Neurosci. 2024;59:2138–2154. doi: 10.1111/ejn.15913. PubMed DOI

Ongnok B., Prathumsap N., Chunchai T., Pantiya P., Arunsak B., Chattipakorn N., Chattipakorn S.C. Nicotinic and Muscarinic Acetylcholine Receptor Agonists Counteract Cognitive Impairment in a Rat Model of Doxorubicin-Induced Chemobrain via Attenuation of Multiple Programmed Cell Death Pathways. Mol. Neurobiol. 2024;61:8831–8850. doi: 10.1007/s12035-024-04145-0. PubMed DOI

Askew C.E., Lopez A.J., Wood M.A., Metherate R. Nicotine Excites VIP Interneurons to Disinhibit Pyramidal Neurons in Auditory Cortex. Synapse. 2019;73:e22116. doi: 10.1002/syn.22116. PubMed DOI PMC

Ghimire M., Cai R., Ling L., Hackett T.A., Caspary D.M. Nicotinic Receptor Subunit Distribution in Auditory Cortex: Impact of Aging on Receptor Number and Function. J. Neurosci. 2020;40:5724–5739. doi: 10.1523/JNEUROSCI.0093-20.2020. PubMed DOI PMC

Counts S.E., He B., Che S., Ikonomovic M.D., DeKosky S.T., Ginsberg S.D., Mufson E.J. Alpha7 Nicotinic Receptor Up-Regulation in Cholinergic Basal Forebrain Neurons in Alzheimer Disease. Arch. Neurol. 2007;64:1771–1776. doi: 10.1001/archneur.64.12.1771. PubMed DOI

Dorszewska J., Florczak J., Rózycka A., Jaroszewska-Kolecka J., Trzeciak W.H., Kozubski W. Polymorphisms of the CHRNA4 Gene Encoding the Alpha4 Subunit of Nicotinic Acetylcholine Receptor as Related to the Oxidative DNA Damage and the Level of Apoptotic Proteins in Lymphocytes of the Patients with Alzheimer’s Disease. DNA Cell Biol. 2005;24:786–794. doi: 10.1089/dna.2005.24.786. PubMed DOI

Dorszewska J., Kempisty B., Jaroszewska-Kolecka J., Rózycka A., Florczak J., Lianeri M., Jagodziński P.P., Kozubski W. Expression and Polymorphisms of Gene 8-Oxoguanine Glycosylase 1 and the Level of Oxidative DNA Damage in Peripheral Blood Lymphocytes of Patients with Alzheimer’s Disease. DNA Cell Biol. 2009;28:579–588. doi: 10.1089/dna.2009.0926. PubMed DOI

Dezor M., Dorszewska J., Florczak J., Kempisty B., Jaroszewska-Kolecka J., Rozycka A., Polrolniczak A., Bugaj R., Jagodzinski P.P., Kozubski W. Expression of 8-Oxoguanine DNA Glycosylase 1 (OGG1) and the Level of P53 and TNF-Alpha Proteins in Peripheral Lymphocytes of Patients with Alzheimer’s Disease. Folia Neuropathol. 2011;49:123–131. PubMed

Dorszewska J., Florczak J., Rozycka A., Kempisty B., Jaroszewska-Kolecka J., Chojnacka K., Trzeciak W.H., Kozubski W. Oxidative DNA Damage and Level of Thiols as Related to Polymorphisms of MTHFR, MTR, MTHFD1 in Alzheimer’s and Parkinson’s Diseases. Acta Neurobiol. Exp. (Wars) 2007;67:113–129. doi: 10.55782/ane-2007-1639. PubMed DOI

Dai Q., Ma Y., Liu C., Zhao R., Chen Q., Chen W., Wang X., Jiang X., Li S. Association of 8-Hydroxy-2’-Deoxyguanosine with Motoric Cognitive Risk in Elderly Chinese People: RUGAO Longevity and Aging Cross-Sectional Study. BMC Geriatr. 2024;24:331. doi: 10.1186/s12877-024-04943-0. PubMed DOI PMC

Sáez G.T. DNA Injury and Repair Systems. Int. J. Mol. Sci. 2018;19:1902. doi: 10.3390/ijms19071902. PubMed DOI PMC

Sas K., Szabó E., Vécsei L. Mitochondria, Oxidative Stress and the Kynurenine System, with a Focus on Ageing and Neuroprotection. Molecules. 2018;23:191. doi: 10.3390/molecules23010191. PubMed DOI PMC

Voskarides K., Giannopoulou N. The Role of TP53 in Adaptation and Evolution. Cells. 2023;12:512. doi: 10.3390/cells12030512. PubMed DOI PMC

Zhao T., Ye S., Tang Z., Guo L., Ma Z., Zhang Y., Yang C., Peng J., Chen J. Loss-of-Function of P53 Isoform Δ113p53 Accelerates Brain Aging in Zebrafish. Cell Death Dis. 2021;12:151. doi: 10.1038/s41419-021-03438-9. PubMed DOI PMC

Dorszewska J., Oczkowska A., Suwalska M., Rozycka A., Florczak-Wyspianska J., Dezor M., Lianeri M., Jagodzinski P.P., Kowalczyk M.J., Prendecki M., et al. Mutations in the Exon 7 of Trp53 Gene and the Level of P53 Protein in Double Transgenic Mouse Model of Alzheimer’s Disease. Folia Neuropathol. 2014;52:30–40. doi: 10.5114/fn.2014.41742. PubMed DOI

Conti P., Ronconi G., Lauritano D., Mastrangelo F., Caraffa A., Gallenga C.E., Frydas I., Kritas S.K., Carinci F., Gaudelli F., et al. Impact of TNF and IL-33 Cytokines on Mast Cells in Neuroinflammation. Int. J. Mol. Sci. 2024;25:3248. doi: 10.3390/ijms25063248. PubMed DOI PMC

Hassamal S. Chronic Stress, Neuroinflammation, and Depression: An Overview of Pathophysiological Mechanisms and Emerging Anti-Inflammatories. Front. Psychiatry. 2023;14:1130989. doi: 10.3389/fpsyt.2023.1130989. PubMed DOI PMC

Lozano-Vicario L., García-Hermoso A., Cedeno-Veloz B.A., Fernández-Irigoyen J., Santamaría E., Romero-Ortuno R., Zambom-Ferraresi F., Sáez de Asteasu M.L., Muñoz-Vázquez Á.J., Izquierdo M., et al. Biomarkers of Delirium Risk in Older Adults: A Systematic Review and Meta-Analysis. Front. Aging Neurosci. 2023;15:1174644. doi: 10.3389/fnagi.2023.1174644. PubMed DOI PMC

Dhapola R., Beura S.K., Sharma P., Singh S.K., HariKrishnaReddy D. Oxidative Stress in Alzheimer’s Disease: Current Knowledge of Signaling Pathways and Therapeutics. Mol. Biol. Rep. 2024;51:48. doi: 10.1007/s11033-023-09021-z. PubMed DOI

Porcher L., Bruckmeier S., Burbano S.D., Finnell J.E., Gorny N., Klett J., Wood S.K., Kelly M.P. Aging Triggers an Upregulation of a Multitude of Cytokines in the Male and Especially the Female Rodent Hippocampus but More Discrete Changes in Other Brain Regions. J. Neuroinflammation. 2021;18:219. doi: 10.1186/s12974-021-02252-6. PubMed DOI PMC

Kozubski W., Ong K., Waleszczyk W., Zabel M., Dorszewska J. Molecular Factors Mediating Neural Cell Plasticity Changes in Dementia Brain Diseases. Neural Plast. 2021;2021:8834645. doi: 10.1155/2021/8834645. PubMed DOI PMC

Karimi Tari P., Parsons C.G., Collingridge G.L., Rammes G. Memantine: Updating a Rare Success Story in pro-Cognitive Therapeutics. Neuropharmacology. 2024;244:109737. doi: 10.1016/j.neuropharm.2023.109737. PubMed DOI

Dąbrowska-Bouta B., Strużyńska L., Sidoryk-Węgrzynowicz M., Sulkowski G. Memantine Modulates Oxidative Stress in the Rat Brain Following Experimental Autoimmune Encephalomyelitis. Int. J. Mol. Sci. 2021;22:11330. doi: 10.3390/ijms222111330. PubMed DOI PMC

Thangwaritorn S., Lee C., Metchikoff E., Razdan V., Ghafary S., Rivera D., Pinto A., Pemminati S. A Review of Recent Advances in the Management of Alzheimer’s Disease. Cureus. 2024;16:e58416. doi: 10.7759/cureus.58416. PubMed DOI PMC

Reuben D.B., Kremen S., Maust D.T. Dementia Prevention and Treatment: A Narrative Review. JAMA Intern. Med. 2024;184:563–572. doi: 10.1001/jamainternmed.2023.8522. PubMed DOI

Buccellato F.R., D’Anca M., Tartaglia G.M., Del Fabbro M., Scarpini E., Galimberti D. Treatment of Alzheimer’s Disease: Beyond Symptomatic Therapies. Int. J. Mol. Sci. 2023;24:13900. doi: 10.3390/ijms241813900. PubMed DOI PMC

Nair A.S., Sahoo R.K. Efficacy of Memantine Hydrochloride in Neuropathic Pain. Indian J. Palliat. Care. 2019;25:161–162. PubMed PMC

Karolczak D., Sawicka E., Dorszewska J., Radel A., Bodnar M., Błaszczyk A., Jagielska J., Marszałek A. Memantine-Neuroprotective Drug in Aging Brain. Pol. J. Pathol. 2013;64:196–203. doi: 10.5114/pjp.2013.38139. PubMed DOI

Xu K., Sun G., Wang Y., Luo H., Wang Y., Liu M., Liu H., Lu X., Qin X. Mitigating Radiation-Induced Brain Injury via NLRP3/NLRC4/Caspase-1 Pyroptosis Pathway: Efficacy of Memantine and Hydrogen-Rich Water. Biomed. Pharmacother. 2024;177:116978. doi: 10.1016/j.biopha.2024.116978. PubMed DOI

Polat İ., Cilaker Mıcılı S., Çalışır M., Bayram E., Yiş U., Ayanoğlu M., Okur D., Edem P., Paketçi C., Tuğyan K., et al. Neuroprotective Effects of Lacosamide and Memantine on Hyperoxic Brain Injury in Rats. Neurochem. Res. 2020;45:1920–1929. doi: 10.1007/s11064-020-03056-5. PubMed DOI

Yıldızhan K., Nazıroğlu M. NMDA Receptor Activation Stimulates Hypoxia-Induced TRPM2 Channel Activation, Mitochondrial Oxidative Stress, and Apoptosis in Neuronal Cell Line: Modular Role of Memantine. Brain Res. 2023;1803:148232. doi: 10.1016/j.brainres.2023.148232. PubMed DOI

Chen B., Wang G., Li W., Liu W., Lin R., Tao J., Jiang M., Chen L., Wang Y. Memantine Attenuates Cell Apoptosis by Suppressing the Calpain-Caspase-3 Pathway in an Experimental Model of Ischemic Stroke. Exp. Cell Res. 2017;351:163–172. doi: 10.1016/j.yexcr.2016.12.028. PubMed DOI

Hasanagic S., Serdarevic F. Potential Role of Memantine in the Prevention and Treatment of COVID-19: Its Antagonism of Nicotinic Acetylcholine Receptors and Beyond. Eur. Respir. J. 2020;56:2001610. doi: 10.1183/13993003.01610-2020. PubMed DOI PMC

Bali Z.K., Bruszt N., Tadepalli S.A., Csurgyók R., Nagy L.V., Tompa M., Hernádi I. Cognitive Enhancer Effects of Low Memantine Doses Are Facilitated by an Alpha7 Nicotinic Acetylcholine Receptor Agonist in Scopolamine-Induced Amnesia in Rats. Front. Pharmacol. 2019;10:73. doi: 10.3389/fphar.2019.00073. PubMed DOI PMC

Ferrer-Acosta Y., Rodriguez-Massó S., Pérez D., Eterovic V.A., Ferchmin P.A., Martins A.H. Memantine Has a Nicotinic Neuroprotective Pathway in Acute Hippocampal Slices After an NMDA Insult. Toxicol. Vitr. 2022;84:105453. doi: 10.1016/j.tiv.2022.105453. PubMed DOI PMC

Rosa A.O., Egea J., Gandía L., López M.G., García A.G. Neuroprotection by Nicotine in Hippocampal Slices Subjected to Oxygen-Glucose Deprivation: Involvement of the Alpha7 nAChR Subtype. J. Mol. Neurosci. 2006;30:61–62. doi: 10.1385/JMN:30:1:61. PubMed DOI

Filley C.M., Fields R.D. White Matter and Cognition: Making the Connection. J. Neurophysiol. 2016;116:2093–2104. doi: 10.1152/jn.00221.2016. PubMed DOI PMC

Arrondo P., Elía-Zudaire Ó., Martí-Andrés G., Fernández-Seara M.A., Riverol M. Grey Matter Changes on Brain MRI in Subjective Cognitive Decline: A Systematic Review. Alzheimers Res. Ther. 2022;14:98. doi: 10.1186/s13195-022-01031-6. PubMed DOI PMC

Navakkode S., Kennedy B.K. Neural Ageing and Synaptic Plasticity: Prioritizing Brain Health in Healthy Longevity. Front. Aging Neurosci. 2024;16:1428244. doi: 10.3389/fnagi.2024.1428244. PubMed DOI PMC

Wang M., Zhang C., Lin S., Xie R. Dendritic Degeneration and Altered Synaptic Innervation of a Central Auditory Neuron During Age-Related Hearing Loss. Neuroscience. 2023;514:25–37. doi: 10.1016/j.neuroscience.2023.01.037. PubMed DOI PMC

Muñoz P., Ardiles Á.O., Pérez-Espinosa B., Núñez-Espinosa C., Paula-Lima A., González-Billault C., Espinosa-Parrilla Y. Redox Modifications in Synaptic Components as Biomarkers of Cognitive Status, in Brain Aging and Disease. Mech. Ageing Dev. 2020;189:111250. doi: 10.1016/j.mad.2020.111250. PubMed DOI

Loreto A., Antoniou C., Merlini E., Gilley J., Coleman M.P. NMN: The NAD Precursor at the Intersection Between Axon Degeneration and Anti-Ageing Therapies. Neurosci. Res. 2023;197:18–24. doi: 10.1016/j.neures.2023.01.004. PubMed DOI

Kirshenbaum G.S., Chang C.-Y., Bompolaki M., Bradford V.R., Bell J., Kosmidis S., Shansky R.M., Orlandi J., Savage L.M., Harris A.Z., et al. Adult-Born Neurons Maintain Hippocampal Cholinergic Inputs and Support Working Memory During Aging. Mol. Psychiatry. 2023;28:5337–5349. doi: 10.1038/s41380-023-02167-z. PubMed DOI

Boisvert M.M., Erikson G.A., Shokhirev M.N., Allen N.J. The Aging Astrocyte Transcriptome from Multiple Regions of the Mouse Brain. Cell Rep. 2018;22:269–285. doi: 10.1016/j.celrep.2017.12.039. PubMed DOI PMC

Kedmi M., Orr-Urtreger A. The Effects of Aging vs. A7 nAChR Subunit Deficiency on the Mouse Brain Transcriptome: Aging Beats the Deficiency. Age. 2011;33:1–13. doi: 10.1007/s11357-010-9155-7. PubMed DOI PMC

Charpantier E., Besnard F., Graham D., Sgard F. Diminution of Nicotinic Receptor Alpha 3 Subunit mRNA Expression in Aged Rat Brain. Brain Res. Dev. Brain Res. 1999;118:153–158. doi: 10.1016/S0165-3806(99)00157-1. PubMed DOI

Tohgi H., Utsugisawa K., Yoshimura M., Nagane Y., Mihara M. Age-Related Changes in Nicotinic Acetylcholine Receptor Subunits Alpha4 and Beta2 Messenger RNA Expression in Postmortem Human Frontal Cortex and Hippocampus. Neurosci. Lett. 1998;245:139–142. doi: 10.1016/S0304-3940(98)00205-5. PubMed DOI

Ferrari R., Pedrazzi P., Algeri S., Agnati L.F., Zoli M. Subunit and Region-Specific Decreases in Nicotinic Acetylcholine Receptor mRNA in the Aged Rat Brain. Neurobiol. Aging. 1999;20:37–46. doi: 10.1016/S0197-4580(99)00015-9. PubMed DOI

Marvanová M., Lakso M., Wong G. Identification of Genes Regulated by Memantine and MK-801 in Adult Rat Brain by cDNA Microarray Analysis. Neuropsychopharmacology. 2004;29:1070–1079. doi: 10.1038/sj.npp.1300398. PubMed DOI

Motawaj M., Burban A., Davenas E., Arrang J.-M. Activation of Brain Histaminergic Neurotransmission: A Mechanism for Cognitive Effects of Memantine in Alzheimer’s Disease. J. Pharmacol. Exp. Ther. 2011;336:479–487. doi: 10.1124/jpet.110.174458. PubMed DOI

Yu W.-F., Nordberg A., Ravid R., Guan Z.-Z. Correlation of Oxidative Stress and the Loss of the Nicotinic Receptor Alpha 4 Subunit in the Temporal Cortex of Patients with Alzheimer’s Disease. Neurosci. Lett. 2003;338:13–16. doi: 10.1016/S0304-3940(02)01361-7. PubMed DOI

Guan Z.-Z., Yu W.-F., Shan K.-R., Nordman T., Olsson J., Nordberg A. Loss of Nicotinic Receptors Induced by Beta-Amyloid Peptides in PC12 Cells: Possible Mechanism Involving Lipid Peroxidation. J. Neurosci. Res. 2003;71:397–406. doi: 10.1002/jnr.10496. PubMed DOI

Yu W.-F., Guan Z.-Z., Bogdanovic N., Nordberg A. High Selective Expression of Alpha7 Nicotinic Receptors on Astrocytes in the Brains of Patients with Sporadic Alzheimer’s Disease and Patients Carrying Swedish APP 670/671 Mutation: A Possible Association with Neuritic Plaques. Exp. Neurol. 2005;192:215–225. doi: 10.1016/j.expneurol.2004.12.015. PubMed DOI

Agulhon C., Sun M.-Y., Murphy T., Myers T., Lauderdale K., Fiacco T.A. Calcium Signaling and Gliotransmission in Normal vs. Reactive Astrocytes. Front. Pharmacol. 2012;3:139. doi: 10.3389/fphar.2012.00139. PubMed DOI PMC

Benz B., Grima G., Do K.Q. Glutamate-Induced Homocysteic Acid Release from Astrocytes: Possible Implication in Glia-Neuron Signaling. Neuroscience. 2004;124:377–386. doi: 10.1016/j.neuroscience.2003.08.067. PubMed DOI

Poddar R., Chen A., Winter L., Rajagopal S., Paul S. Role of AMPA Receptors in Homocysteine-NMDA Receptor-Induced Crosstalk Between ERK and P38 MAPK. J. Neurochem. 2017;142:560–573. doi: 10.1111/jnc.14078. PubMed DOI PMC

Jara-Prado A., Ortega-Vazquez A., Martinez-Ruano L., Rios C., Santamaria A. Homocysteine-Induced Brain Lipid Peroxidation: Effects of NMDA Receptor Blockade, Antioxidant Treatment, and Nitric Oxide Synthase Inhibition. Neurotox. Res. 2003;5:237–243. doi: 10.1007/BF03033381. PubMed DOI

Smith A.D., Refsum H. Homocysteine-from Disease Biomarker to Disease Prevention. J. Intern. Med. 2021;290:826–854. doi: 10.1111/joim.13279. PubMed DOI

Tawfik A., Elsherbiny N.M., Zaidi Y., Rajpurohit P. Homocysteine and Age-Related Central Nervous System Diseases: Role of Inflammation. Int. J. Mol. Sci. 2021;22:6259. doi: 10.3390/ijms22126259. PubMed DOI PMC

Jakubowski H. Homocysteine Thiolactone Detoxifying Enzymes and Alzheimer’s Disease. Int. J. Mol. Sci. 2024;25:8095. doi: 10.3390/ijms25158095. PubMed DOI PMC

Ting C.-P., Ma M.-C., Chang H.-I., Huang C.-W., Chou M.-C., Chang C.-C. Diet Pattern Analysis in Alzheimer’s Disease Implicates Gender Differences in Folate-B12-Homocysteine Axis on Cognitive Outcomes. Nutrients. 2024;16:733. doi: 10.3390/nu16050733. PubMed DOI PMC

Joshi S.M., Jadavji N.M. Deficiencies in One-Carbon Metabolism Led to Increased Neurological Disease Risk and Worse Outcome: Homocysteine Is a Marker of Disease State. Front. Nutr. 2024;11:1285502. doi: 10.3389/fnut.2024.1285502. PubMed DOI PMC

Tudek B., Zdżalik-Bielecka D., Tudek A., Kosicki K., Fabisiewicz A., Speina E. Lipid Peroxidation in Face of DNA Damage, DNA Repair and Other Cellular Processes. Free Radic. Biol. Med. 2017;107:77–89. doi: 10.1016/j.freeradbiomed.2016.11.043. PubMed DOI

Nunomura A., Tamaoki T., Motohashi N., Nakamura M., McKeel D.W., Tabaton M., Lee H.-G., Smith M.A., Perry G., Zhu X. The Earliest Stage of Cognitive Impairment in Transition from Normal Aging to Alzheimer Disease Is Marked by Prominent RNA Oxidation in Vulnerable Neurons. J. Neuropathol. Exp. Neurol. 2012;71:233–241. doi: 10.1097/NEN.0b013e318248e614. PubMed DOI PMC

Gredilla R., Garm C., Stevnsner T. Nuclear and Mitochondrial DNA Repair in Selected Eukaryotic Aging Model Systems. Oxid. Med. Cell. Longev. 2012;2012:282438. doi: 10.1155/2012/282438. PubMed DOI PMC

Chaudhary M.R., Chaudhary S., Sharma Y., Singh T.A., Mishra A.K., Sharma S., Mehdi M.M. Aging, Oxidative Stress and Degenerative Diseases: Mechanisms, Complications and Emerging Therapeutic Strategies. Biogerontology. 2023;24:609–662. doi: 10.1007/s10522-023-10050-1. PubMed DOI

Pao P.-C., Patnaik D., Watson L.A., Gao F., Pan L., Wang J., Adaikkan C., Penney J., Cam H.P., Huang W.-C., et al. HDAC1 Modulates OGG1-Initiated Oxidative DNA Damage Repair in the Aging Brain and Alzheimer’s Disease. Nat. Commun. 2020;11:2484. doi: 10.1038/s41467-020-16361-y. PubMed DOI PMC

Ames B.N., Shigenaga M.K., Hagen T.M. Oxidants, Antioxidants, and the Degenerative Diseases of Aging. Proc. Natl. Acad. Sci. USA. 1993;90:7915–7922. doi: 10.1073/pnas.90.17.7915. PubMed DOI PMC

Fraga C.G., Shigenaga M.K., Park J.W., Degan P., Ames B.N. Oxidative Damage to DNA During Aging: 8-Hydroxy-2’-Deoxyguanosine in Rat Organ DNA and Urine. Proc. Natl. Acad. Sci. USA. 1990;87:4533–4537. doi: 10.1073/pnas.87.12.4533. PubMed DOI PMC

Dorszewska J., Adamczewska-Goncerzewicz Z. Oxidative Damage to DNA, P53 Gene Expression and P53 Protein Level in the Process of Aging in Rat Brain. Respir. Physiol. Neurobiol. 2004;139:227–236. doi: 10.1016/j.resp.2003.10.005. PubMed DOI

Cooper C.P., Cheng L.H., Bhatti J.A., Rivera E.L., Huell D., Banuelos C., Perez E.J., Long J.M., Rapp P.R. Cerebellum Purkinje Cell Vulnerability in Aged Rats with Memory Impairment. J. Comp. Neurol. 2024;532:e25610. doi: 10.1002/cne.25610. PubMed DOI PMC

Castejón O.J. Ultrastructural Pathology of Human Peritumoural Oedematous Cerebellar Cortex. Folia Neuropathol. 2016;54:127–136. doi: 10.5114/fn.2016.60057. PubMed DOI

Kakizawa S., Shibazaki M., Mori N. Protein Oxidation Inhibits NO-Mediated Signaling Pathway for Synaptic Plasticity. Neurobiol. Aging. 2012;33:535–545. doi: 10.1016/j.neurobiolaging.2010.04.016. PubMed DOI

Fornasari E., Marinelli L., Di Stefano A., Eusepi P., Turkez H., Fulle S., Di Filippo E.S., Scarabeo A., Di Nicola S., Cacciatore I. Synthesis and Antioxidant Properties of Novel Memantine Derivatives. Cent. Nerv. Syst. Agents Med. Chem. 2017;17:123–128. doi: 10.2174/1871524916666160625123621. PubMed DOI

Koola M.M., Praharaj S.K., Pillai A. Galantamine-Memantine Combination as an Antioxidant Treatment for Schizophrenia. Curr. Behav. Neurosci. Rep. 2019;6:37–50. doi: 10.1007/s40473-019-00174-5. PubMed DOI PMC

Sozio P., Cerasa L.S., Laserra S., Cacciatore I., Cornacchia C., Di Filippo E.S., Fulle S., Fontana A., Di Crescenzo A., Grilli M., et al. Memantine-Sulfur Containing Antioxidant Conjugates as Potential Prodrugs to Improve the Treatment of Alzheimer’s Disease. Eur. J. Pharm. Sci. 2013;49:187–198. doi: 10.1016/j.ejps.2013.02.013. PubMed DOI

Liu W., Xu Z., Yang T., Xu B., Deng Y., Feng S. Memantine, a Low-Affinity NMDA Receptor Antagonist, Protects against Methylmercury-Induced Cytotoxicity of Rat Primary Cultured Cortical Neurons, Involvement of Ca2+ Dyshomeostasis Antagonism, and Indirect Antioxidation Effects. Mol. Neurobiol. 2017;54:5034–5050. doi: 10.1007/s12035-016-0020-2. PubMed DOI

Hussain M., Chu X., Duan Sahbaz B., Gray S., Pekhale K., Park J.-H., Croteau D.L., Bohr V.A. Mitochondrial OGG1 Expression Reduces Age-Associated Neuroinflammation by Regulating Cytosolic Mitochondrial DNA. Free Radic. Biol. Med. 2023;203:34–44. doi: 10.1016/j.freeradbiomed.2023.03.262. PubMed DOI PMC

Iida T., Furuta A., Nishioka K., Nakabeppu Y., Iwaki T. Expression of 8-Oxoguanine DNA Glycosylase Is Reduced and Associated with Neurofibrillary Tangles in Alzheimer’s Disease Brain. Acta Neuropathol. 2002;103:20–25. doi: 10.1007/s004010100418. PubMed DOI

Mehta S., Campbell H., Drummond C.J., Li K., Murray K., Slatter T., Bourdon J.-C., Braithwaite A.W. Adaptive Homeostasis and the P53 Isoform Network. EMBO Rep. 2021;22:e53085. doi: 10.15252/embr.202153085. PubMed DOI PMC

Achanta G., Huang P. Role of P53 in Sensing Oxidative DNA Damage in Response to Reactive Oxygen Species-Generating Agents. Cancer Res. 2004;64:6233–6239. doi: 10.1158/0008-5472.CAN-04-0494. PubMed DOI

Chatterjee A., Mambo E., Osada M., Upadhyay S., Sidransky D. The Effect of P53-RNAi and P53 Knockout on Human 8-Oxoguanine DNA Glycosylase (hOgg1) Activity. FASEB J. 2006;20:112–114. doi: 10.1096/fj.04-3423fje. PubMed DOI

Zhang Y., McLaughlin R., Goodyer C., LeBlanc A. Selective Cytotoxicity of Intracellular Amyloid Beta Peptide1-42 Through P53 and Bax in Cultured Primary Human Neurons. J. Cell Biol. 2002;156:519–529. doi: 10.1083/jcb.200110119. PubMed DOI PMC

Ioudina M., Uemura E. A Three Amino Acid Peptide, Gly-Pro-Arg, Protects and Rescues Cell Death Induced by Amyloid Beta-Peptide. Exp. Neurol. 2003;184:923–929. doi: 10.1016/S0014-4886(03)00314-5. PubMed DOI

de la Monte S.M., Wands J.R. Molecular Indices of Oxidative Stress and Mitochondrial Dysfunction Occur Early and Often Progress with Severity of Alzheimer’s Disease. J. Alzheimers Dis. 2006;9:167–181. doi: 10.3233/JAD-2006-9209. PubMed DOI

Liu X., Buffington J.A., Tjalkens R.B. NF-kappaB-Dependent Production of Nitric Oxide by Astrocytes Mediates Apoptosis in Differentiated PC12 Neurons Following Exposure to Manganese and Cytokines. Brain Res. Mol. Brain Res. 2005;141:39–47. doi: 10.1016/j.molbrainres.2005.07.017. PubMed DOI

Kumawat K.L., Kaushik D.K., Goswami P., Basu A. Acute Exposure to Lead Acetate Activates Microglia and Induces Subsequent Bystander Neuronal Death via Caspase-3 Activation. Neurotoxicology. 2014;41:143–153. doi: 10.1016/j.neuro.2014.02.002. PubMed DOI

Zhang L., Dong L.-Y., Li Y.-J., Hong Z., Wei W.-S. The microRNA miR-181c Controls Microglia-Mediated Neuronal Apoptosis by Suppressing Tumor Necrosis Factor. J. Neuroinflamm. 2012;9:211. doi: 10.1186/1742-2094-9-211. PubMed DOI PMC

Maccioni R.B., Rojo L.E., Fernández J.A., Kuljis R.O. The Role of Neuroimmunomodulation in Alzheimer’s Disease. Ann. N. Y. Acad. Sci. 2009;1153:240–246. doi: 10.1111/j.1749-6632.2008.03972.x. PubMed DOI

Morales I., Farías G., Maccioni R.B. Neuroimmunomodulation in the Pathogenesis of Alzheimer’s Disease. Neuroimmunomodulation. 2010;17:202–204. doi: 10.1159/000258724. PubMed DOI

Shen J., Lai W., Li Z., Zhu W., Bai X., Yang Z., Wang Q., Ji J. SDS3 Regulates Microglial Inflammation by Modulating the Expression of the Upstream Kinase ASK1 in the P38 MAPK Signaling Pathway. Inflamm. Res. 2024;73:1547–1564. doi: 10.1007/s00011-024-01913-5. PubMed DOI PMC

Agostinho P., Cunha R.A., Oliveira C. Neuroinflammation, Oxidative Stress and the Pathogenesis of Alzheimer’s Disease. Curr. Pharm. Des. 2010;16:2766–2778. doi: 10.2174/138161210793176572. PubMed DOI

Andrade-Guerrero J., Santiago-Balmaseda A., Jeronimo-Aguilar P., Vargas-Rodríguez I., Cadena-Suárez A.R., Sánchez-Garibay C., Pozo-Molina G., Méndez-Catalá C.F., Cardenas-Aguayo M.-D.-C., Diaz-Cintra S., et al. Alzheimer’s Disease: An Updated Overview of Its Genetics. Int. J. Mol. Sci. 2023;24:3754. doi: 10.3390/ijms24043754. PubMed DOI PMC

Harold D., Abraham R., Hollingworth P., Sims R., Gerrish A., Hamshere M.L., Pahwa J.S., Moskvina V., Dowzell K., Williams A., et al. Genome-Wide Association Study Identifies Variants at CLU and PICALM Associated with Alzheimer’s Disease. Nat. Genet. 2009;41:1088–1093. doi: 10.1038/ng.440. PubMed DOI PMC

Lambert J.-C., Heath S., Even G., Campion D., Sleegers K., Hiltunen M., Combarros O., Zelenika D., Bullido M.J., Tavernier B., et al. Genome-Wide Association Study Identifies Variants at CLU and CR1 Associated with Alzheimer’s Disease. Nat. Genet. 2009;41:1094–1099. doi: 10.1038/ng.439. PubMed DOI

Puerta R., de Rojas I., García-González P., Olivé C., Sotolongo-Grau O., García-Sánchez A., García-Gutiérrez F., Montrreal L., Pablo Tartari J., Sanabria Á., et al. Connecting Genomic and Proteomic Signatures of Amyloid Burden in the Brain. medRxiv. 2024 doi: 10.1101/2024.09.06.24313124. DOI

Verma V., Singh D., Kh R. Sinapic Acid Alleviates Oxidative Stress and Neuro-Inflammatory Changes in Sporadic Model of Alzheimer’s Disease in Rats. Brain Sci. 2020;10:923. doi: 10.3390/brainsci10120923. PubMed DOI PMC

Zeb Z., Sharif A., Akhtar B., Shahnaz 3-Acetyl Coumarin Alleviate Neuroinflammatory Responses and Oxidative Stress in Aluminum Chloride-Induced Alzheimer’s Disease Rat Model. Inflammopharmacology. 2024;32:1371–1386. doi: 10.1007/s10787-024-01434-x. PubMed DOI

Che H., Li Q., Zhang T., Ding L., Zhang L., Shi H., Yanagita T., Xue C., Chang Y., Wang Y. A Comparative Study of EPA-Enriched Ethanolamine Plasmalogen and EPA-Enriched Phosphatidylethanolamine on Aβ42 Induced Cognitive Deficiency in a Rat Model of Alzheimer’s Disease. Food Funct. 2018;9:3008–3017. doi: 10.1039/C8FO00643A. PubMed DOI

Yuan C., Dai C., Li Z., Zheng L., Zhao M., Dong S. Bexarotene Improve Depression-Like Behaviour in Mice by Protecting Against Neuro-Inflammation and Synaptic Damage. Neurochem. Res. 2020;45:1500–1509. doi: 10.1007/s11064-020-03012-3. PubMed DOI

Mabley J.G., Pacher P., Deb A., Wallace R., Elder R.H., Szabó C. Potential Role for 8-Oxoguanine DNA Glycosylase in Regulating Inflammation. FASEB J. 2005;19:290–292. doi: 10.1096/fj.04-2278fje. PubMed DOI

Touati E., Michel V., Thiberge J.-M., Avé P., Huerre M., Bourgade F., Klungland A., Labigne A. Deficiency in OGG1 Protects Against Inflammation and Mutagenic Effects Associated with H. Pylori Infection in Mouse. Helicobacter. 2006;11:494–505. doi: 10.1111/j.1523-5378.2006.00442.x. PubMed DOI

Pan L., Vlahopoulos S., Tanner L., Bergwik J., Bacsi A., Radak Z., Egesten A., Ba X., Brasier A.R., Boldogh I. Substrate-Specific Binding of 8-Oxoguanine DNA Glycosylase 1 (OGG1) Reprograms Mucosal Adaptations to Chronic Airway Injury. Front. Immunol. 2023;14:1186369. doi: 10.3389/fimmu.2023.1186369. PubMed DOI PMC

Lowry O.H., Rosebrough N.J., Farr A.L., Randall R.J. Protein Measurement with the Folin Phenol Reagent. J. Biol. Chem. 1951;193:265–275. doi: 10.1016/S0021-9258(19)52451-6. PubMed DOI

Dorszewska J., Adamczewska-Goncerzewicz Z., Szczech J. Apoptotic Proteins in the Course of Aging of Central Nervous System in the Rat. Respir. Physiol. Neurobiol. 2004;139:145–155. doi: 10.1016/j.resp.2003.10.009. PubMed DOI

Chomczynski P., Sacchi N. Single-Step Method of RNA Isolation by Acid Guanidinium Thiocyanate-Phenol-Chloroform Extraction. Anal. Biochem. 1987;162:156–159. doi: 10.1016/0003-2697(87)90021-2. PubMed DOI

Shimoyama M., De Pons J., Hayman G.T., Laulederkind S.J.F., Liu W., Nigam R., Petri V., Smith J.R., Tutaj M., Wang S.-J., et al. The Rat Genome Database 2015: Genomic, Phenotypic and Environmental Variations and Disease. Nucleic Acids Res. 2015;43:D743–D750. doi: 10.1093/nar/gku1026. PubMed DOI PMC

Kwon N., Lee K.E., Singh M., Kang S.G. Suitable Primers for GAPDH Reference Gene Amplification in Quantitative RT-PCR Analysis of Human Gene Expression. Gene Rep. 2021;24:101272. doi: 10.1016/j.genrep.2021.101272. DOI

Leadon S.A., Cerutti P.A. A rapid and mild procedure for the isolation of DNA from mammalian cells. Anal. Biochem. 1982;120:282–288. doi: 10.1016/0003-2697(82)90349-9. PubMed DOI