The term neuroinflammation defines the reactions of astrocytes and microglia to alterations in homeostasis in the diseased central nervous system (CNS), the exacerbation of which contributes to the neurodegenerative effects of Alzheimer's disease (AD). Local environmental conditions, such as the presence of proinflammatory molecules, mechanical properties of the extracellular matrix (ECM), and local cell-cell interactions, are determinants of glial cell phenotypes. In AD, the load of the cytotoxic/proinflammatory amyloid β (Aβ) peptide is a microenvironmental component increasingly growing in the CNS, imposing time-evolving challenges on resident cells. This study aimed to investigate the temporal and spatial variations of the effects produced by this process on astrocytes and microglia, either directly or by interfering in their interactions. Ex vivo confocal analyses of hippocampal sections from the mouse model TgCRND8 at different ages have shown that overproduction of Aβ peptide induced early and time-persistent disassembly of functional astroglial syncytium and promoted a senile phenotype of reactive microglia, hindering Aβ clearance. In the late stages of the disease, these patterns were altered in the presence of Aβ-plaques, surrounded by typically reactive astrocytes and microglia. Morphofunctional characterization of peri-plaque gliosis revealed a direct contribution of astrocytes in plaque buildup that might result in shielding Aβ-peptide cytotoxicity and, as a side effect, in exacerbating neuroinflammation.

Department of Anatomy 3rd Faculty of Medicine Charles University 100 00 Prague Czech Republic

Department of Biology University of Florence 50121 Florence Italy

Department of Experimental and Clinical Biomedical Sciences University of Florence 50134 Florence Italy

Department of Experimental and Clinical Medicine University of Florence 50134 Florence Italy

Department of Health Sciences University of Florence 50134 Florence Italy

Department of Neuroscience Psychology Drug Research and Child Health University of Florence 50134 Florence Italy

DMSC Imaging Platform 50134 Florence Italy

General Laboratory Careggi University Hospital 50134 Florence Italy

See more in PubMed

McGeer P.L., Itagaki S., Tago H., McGeer E.G. Reactive Microglia in Patients with Senile Dementia of the Alzheimer Type Are Positive for the Histocompatibility Glycoprotein HLA-DR. Neurosci. Lett. 1987;79:195–200. doi: 10.1016/0304-3940(87)90696-3. PubMed DOI

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

Tian L., Ma L., Kaarela T., Li Z. Neuroimmune Crosstalk in the Central Nervous System and Its Significance for Neurological Diseases. J. Neuroinflamm. 2012;9:594. doi: 10.1186/1742-2094-9-155. PubMed DOI PMC

Hanisch U.-K., Kettenmann H. Microglia: Active Sensor and Versatile Effector Cells in the Normal and Pathologic Brain. Nat. Neurosci. 2007;10:1387–1394. doi: 10.1038/nn1997. PubMed DOI

Fu R., Shen Q., Xu P., Luo J.J., Tang Y. Phagocytosis of Microglia in the Central Nervous System Diseases. Mol. Neurobiol. 2014;49:1422–1434. doi: 10.1007/s12035-013-8620-6. PubMed DOI PMC

Thal D.R. The Role of Astrocytes in Amyloid β-Protein Toxicity and Clearance. Exp. Neurol. 2012;236:1–5. doi: 10.1016/j.expneurol.2012.04.021. PubMed DOI

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

Liu W., Tang Y., Feng J. Cross Talk between Activation of Microglia and Astrocytes in Pathological Conditions in the Central Nervous System. Life Sci. 2011;89:141–146. doi: 10.1016/j.lfs.2011.05.011. PubMed DOI

Cerbai F., Lana D., Nosi D., Petkova-Kirova P., Zecchi S., Brothers H.M., Wenk G.L., Giovannini M.G. The Neuron-Astrocyte-Microglia Triad in Normal Brain Ageing and in a Model of Neuroinflammation in the Rat Hippocampus. PLoS ONE. 2012;7:e45250. doi: 10.1371/journal.pone.0045250. PubMed DOI PMC

Lana D., Ugolini F., Wenk G.L., Giovannini M.G., Zecchi-Orlandini S., Nosi D. Microglial Distribution, Branching, and Clearance Activity in Aged Rat Hippocampus Are Affected by Astrocyte Meshwork Integrity: Evidence of a Novel Cell-cell Interglial Interaction. FASEB J. 2019;33:4007–4020. doi: 10.1096/fj.201801539R. PubMed DOI

Ugolini F., Lana D., Nardiello P., Nosi D., Pantano D., Casamenti F., Giovannini M.G. Different Patterns of Neurodegeneration and Glia Activation in CA1 and CA3 Hippocampal Regions of TgCRND8 Mice. Front. Aging Neurosci. 2018;10:372. doi: 10.3389/fnagi.2018.00372. PubMed DOI PMC

Nosi D., Lana D., Giovannini M.G., Delfino G., Zecchi-Orlandini S. Neuroinflammation: Integrated Nervous Tissue Response through Intercellular Interactions at the “Whole System” Scale. Cells. 2021;10:1195. doi: 10.3390/cells10051195. PubMed DOI PMC

Giunta B., Fernandez F., Nikolic W.V., Obregon D., Rrapo E., Town T., Tan J. Inflammaging as a Prodrome to Alzheimer’s Disease. J. Neuroinflamm. 2008;5:51. doi: 10.1186/1742-2094-5-51. PubMed DOI PMC

Deleidi M., Jäggle M., Rubino G. Immune Aging, Dysmetabolism, and Inflammation in Neurological Diseases. Front. Neurosci. 2015;9:172. doi: 10.3389/fnins.2015.00172. PubMed DOI PMC

Neher J.J., Neniskyte U., Brown G.C. Primary Phagocytosis of Neurons by Inflamed Microglia: Potential Roles in Neurodegeneration. Front. Pharmacol. 2012;3:27. doi: 10.3389/fphar.2012.00027. PubMed DOI PMC

Vilalta A., Brown G.C. Neurophagy, the Phagocytosis of Live Neurons and Synapses by Glia, Contributes to Brain Development and Disease. FEBS J. 2018;285:3566–3575. doi: 10.1111/febs.14323. PubMed DOI

Brown G.C., Neher J.J. Microglial Phagocytosis of Live Neurons. Nat. Rev. Neurosci. 2014;15:209–216. doi: 10.1038/nrn3710. PubMed DOI

Mills C.D., Kincaid K., Alt J.M., Heilman M.J., Hill A.M. M-1/M-2 Macrophages and the Th1/Th2 Paradigm. J. Immunol. 2000;164:6166–6173. doi: 10.4049/jimmunol.164.12.6166. PubMed DOI

Colonna M., Butovsky O. Microglia Function in the Central Nervous System During Health and Neurodegeneration. Annu. Rev. Immunol. 2017;35:441–468. doi: 10.1146/annurev-immunol-051116-052358. PubMed DOI PMC

Del Mar Fernández-Arjona M., Grondona J.M., Granados-Durán P., Fernández-Llebrez P., López-Ávalos M.D. Microglia Morphological Categorization in a Rat Model of Neuroinflammation by Hierarchical Cluster and Principal Components Analysis. Front. Cell. Neurosci. 2017;11:235. doi: 10.3389/fncel.2017.00235. PubMed DOI PMC

Matsumoto Y., Ohmori K., Fujiwara M. Microglial and Astroglial Reactions to Inflammatory Lesions of Experimental Autoimmune Encephalomyelitis in the Rat Central Nervous System. J. Neuroimmunol. 1992;37:23–33. doi: 10.1016/0165-5728(92)90152-B. PubMed DOI

Sofroniew M.V. Molecular Dissection of Reactive Astrogliosis and Glial Scar Formation. Trends Neurosci. 2009;32:638–647. doi: 10.1016/j.tins.2009.08.002. PubMed DOI PMC

Liddelow S.A., Barres B.A. Reactive Astrocytes: Production, Function, and Therapeutic Potential. Immunity. 2017;46:957–967. doi: 10.1016/j.immuni.2017.06.006. PubMed DOI

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

Wheeler M.A., Clark I.C., Tjon E.C., Li Z., Zandee S.E.J., Couturier C.P., Watson B.R., Scalisi G., Alkwai S., Rothhammer V., et al. MAFG-Driven Astrocytes Promote CNS Inflammation. Nature. 2020;578:593–599. doi: 10.1038/s41586-020-1999-0. PubMed DOI PMC

Ma B., Buckalew R., Du Y., Kiyoshi C.M., Alford C.C., Wang W., McTigue D.M., Enyeart J.J., Terman D., Zhou M. Gap Junction Coupling Confers Isopotentiality on Astrocyte Syncytium: Electrical Coupling of Astrocytes in a Syncytium. Glia. 2016;64:214–226. doi: 10.1002/glia.22924. PubMed DOI PMC

Rasmussen M.K., Mestre H., Nedergaard M. Fluid Transport in the Brain. Physiol. Rev. 2022;102:1025–1151. doi: 10.1152/physrev.00031.2020. PubMed DOI PMC

Fróes M.M., Correia A.H.P., Garcia-Abreu J., Spray D.C., Campos de Carvalho A.C., Neto V.M. Gap-Junctional Coupling between Neurons and Astrocytes in Primary Central Nervous System Cultures. Proc. Natl. Acad. Sci. USA. 1999;96:7541–7546. doi: 10.1073/pnas.96.13.7541. PubMed DOI PMC

Mercatelli R., Lana D., Bucciantini M., Giovannini M.G., Cerbai F., Quercioli F., Zecchi-Orlandini S., Delfino G., Wenk G.L., Nosi D. Clasmatodendrosis and Β-amyloidosis in Aging Hippocampus. FASEB J. 2016;30:1480–1491. doi: 10.1096/fj.15-275503. PubMed DOI

Hulse R.E., Winterfield J., Kunkler P.E., Kraig R.P. Astrocytic Clasmatodendrosis in Hippocampal Organ Culture. Glia. 2001;33:169–179. doi: 10.1002/1098-1136(200102)33:2<169::AID-GLIA1016>3.0.CO;2-B. 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

Yoshiyama Y., Asahina M., Hattori T. Selective Distribution of Matrix Metalloproteinase-3 (MMP-3) in Alzheimer’s Disease Brain. Acta Neuropathol. 2000;99:91–95. doi: 10.1007/PL00007428. PubMed DOI

Palmer J.C., Baig S., Kehoe P.G., Love S. Endothelin-Converting Enzyme-2 Is Increased in Alzheimer’s Disease and Up-Regulated by Aβ. Am. J. Pathol. 2009;175:262–270. doi: 10.2353/ajpath.2009.081054. PubMed DOI PMC

Nielsen H.M., Veerhuis R., Holmqvist B., Janciauskiene S. Binding and Uptake of Aβ1-42 by Primary Human Astrocytes In Vitro. Glia. 2009;57:978–988. doi: 10.1002/glia.20822. PubMed DOI

Zhao J., O’Connor T., Vassar R. The Contribution of Activated Astrocytes to Aβ Production: Implications for Alzheimer’s Disease Pathogenesis. J. Neuroinflamm. 2011;8:150. doi: 10.1186/1742-2094-8-150. PubMed DOI PMC

Yan P., Bero A.W., Cirrito J.R., Xiao Q., Hu X., Wang Y., Gonzales E., Holtzman D.M., Lee J.-M. Characterizing the Appearance and Growth of Amyloid Plaques in APP/PS1 Mice. J. Neurosci. 2009;29:10706–10714. doi: 10.1523/JNEUROSCI.2637-09.2009. 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

Guttenplan K.A., Weigel M.K., Prakash P., Wijewardhane P.R., Hasel P., Rufen-Blanchette U., Münch A.E., Blum J.A., Fine J., Neal M.C., et al. Neurotoxic Reactive Astrocytes Induce Cell Death via Saturated Lipids. Nature. 2021;599:102–107. doi: 10.1038/s41586-021-03960-y. PubMed DOI

Wang C., Xiong M., Gratuze M., Bao X., Shi Y., Andhey P.S., Manis M., Schroeder C., Yin Z., Madore C., et al. Selective Removal of Astrocytic APOE4 Strongly Protects against Tau-Mediated Neurodegeneration and Decreases Synaptic Phagocytosis by Microglia. Neuron. 2021;109:1657–1674.e7. doi: 10.1016/j.neuron.2021.03.024. PubMed DOI PMC

Wang H., Kulas J.A., Wang C., Holtzman D.M., Ferris H.A., Hansen S.B. Regulation of Beta-Amyloid Production in Neurons by Astrocyte-Derived Cholesterol. Proc. Natl. Acad. Sci. USA. 2021;118:e2102191118. doi: 10.1073/pnas.2102191118. PubMed DOI PMC

Pardo A.C., Wong V., Benson L.M., Dykes M., Tanaka K., Rothstein J.D., Maragakis N.J. Loss of the Astrocyte Glutamate Transporter GLT1 Modifies Disease in SOD1G93A Mice. Exp. Neurol. 2006;201:120–130. doi: 10.1016/j.expneurol.2006.03.028. PubMed DOI

Matos M., Augusto E., Oliveira C.R., Agostinho P. Amyloid-Beta Peptide Decreases Glutamate Uptake in Cultured Astrocytes: Involvement of Oxidative Stress and Mitogen-Activated Protein Kinase Cascades. Neuroscience. 2008;156:898–910. doi: 10.1016/j.neuroscience.2008.08.022. PubMed DOI

Tong X., Ao Y., Faas G.C., Nwaobi S.E., Xu J., Haustein M.D., Anderson M.A., Mody I., Olsen M.L., Sofroniew M.V., et al. Astrocyte Kir4.1 Ion Channel Deficits Contribute to Neuronal Dysfunction in Huntington’s Disease Model Mice. Nat. Neurosci. 2014;17:694–703. doi: 10.1038/nn.3691. PubMed DOI PMC

Chazalon M., Paredes-Rodriguez E., Morin S., Martinez A., Cristóvão-Ferreira S., Vaz S., Sebastiao A., Panatier A., Boué-Grabot E., Miguelez C., et al. GAT-3 Dysfunction Generates Tonic Inhibition in External Globus Pallidus Neurons in Parkinsonian Rodents. Cell Rep. 2018;23:1678–1690. doi: 10.1016/j.celrep.2018.04.014. PubMed DOI

Chao C.-C., Gutiérrez-Vázquez C., Rothhammer V., Mayo L., Wheeler M.A., Tjon E.C., Zandee S.E.J., Blain M., de Lima K.A., Takenaka M.C., et al. Metabolic Control of Astrocyte Pathogenic Activity via CPLA2-MAVS. Cell. 2019;179:1483–1498.e22. doi: 10.1016/j.cell.2019.11.016. PubMed DOI PMC

Polyzos A.A., Lee D.Y., Datta R., Hauser M., Budworth H., Holt A., Mihalik S., Goldschmidt P., Frankel K., Trego K., et al. Metabolic Reprogramming in Astrocytes Distinguishes Region-Specific Neuronal Susceptibility in Huntington Mice. Cell Metab. 2019;29:1258–1273.e11. doi: 10.1016/j.cmet.2019.03.004. PubMed DOI PMC

Chishti M.A., Yang D.-S., Janus C., Phinney A.L., Horne P., Pearson J., Strome R., Zuker N., Loukides J., French J., et al. Early-Onset Amyloid Deposition and Cognitive Deficits in Transgenic Mice Expressing a Double Mutant Form of Amyloid Precursor Protein 695*. J. Biol. Chem. 2001;276:21562–21570. doi: 10.1074/jbc.M100710200. PubMed DOI

Bellucci A., Luccarini I., Scali C., Prosperi C., Giovannini M.G., Pepeu G., Casamenti F. Cholinergic Dysfunction, Neuronal Damage and Axonal Loss in TgCRND8 Mice. Neurobiol. Dis. 2006;23:260–272. doi: 10.1016/j.nbd.2006.03.012. PubMed DOI

Hamm V., Héraud C., Bott J.-B., Herbeaux K., Strittmatter C., Mathis C., Goutagny R. Differential Contribution of APP Metabolites to Early Cognitive Deficits in a TgCRND8 Mouse Model of Alzheimer’s Disease. Sci. Adv. 2017;3:e1601068. doi: 10.1126/sciadv.1601068. PubMed DOI PMC

Giovannini M.G. Double-Label Confocal Microscopy of Phosphorylated Protein Kinases Involved in Long-Term Potentiation. In: Iyengar R., Hildebrandt J.D., editors. Methods in Enzymology. Volume 345. Academic Press; Cambridge, MA, USA: 2002. pp. 426–436. G Protein Pathways. PubMed

Schindelin J., Arganda-Carreras I., Frise E., Kaynig V., Longair M., Pietzsch T., Preibisch S., Rueden C., Saalfeld S., Schmid B., et al. Fiji: An Open-Source Platform for Biological-Image Analysis. Nat. Methods. 2012;9:676–682. doi: 10.1038/nmeth.2019. PubMed DOI PMC

Arshadi C., Günther U., Eddison M., Harrington K.I.S., Ferreira T.A. SNT: A Unifying Toolbox for Quantification of Neuronal Anatomy. Nat. Methods. 2021;18:374–377. doi: 10.1038/s41592-021-01105-7. PubMed DOI

Ferreira T.A., Blackman A.V., Oyrer J., Jayabal S., Chung A.J., Watt A.J., Sjöström P.J., van Meyel D.J. Neuronal Morphometry Directly from Bitmap Images. Nat. Methods. 2014;11:982–984. doi: 10.1038/nmeth.3125. PubMed DOI PMC

Olabarria M., Noristani H.N., Verkhratsky A., Rodríguez J.J. Concomitant Astroglial Atrophy and Astrogliosis in a Triple Transgenic Animal Model of Alzheimer’s Disease. Glia. 2010;58:831–838. doi: 10.1002/glia.20967. PubMed DOI

Nguyen P.T., Dorman L.C., Pan S., Vainchtein I.D., Han R.T., Nakao-Inoue H., Taloma S.E., Barron J.J., Molofsky A.B., Kheirbek M.A., et al. Microglial Remodeling of the Extracellular Matrix Promotes Synapse Plasticity. Cell. 2020;182:388–403.e15. doi: 10.1016/j.cell.2020.05.050. PubMed DOI PMC

Verkhratsky A., Rodrigues J.J., Pivoriunas A., Zorec R., Semyanov A. Astroglial Atrophy in Alzheimer’s Disease. Pflügers Arch. Eur. J. Physiol. 2019;471:1247–1261. doi: 10.1007/s00424-019-02310-2. PubMed DOI

Nagy J.I., Li W., Hertzberg E.L., Marotta C.A. Elevated Connexin43 Immunoreactivity at Sites of Amyloid Plaques in Alzheimer’s Disease. Brain Res. 1996;717:173–178. doi: 10.1016/0006-8993(95)01526-4. PubMed DOI

Cibelli A., Stout R., Timmermann A., de Menezes L., Guo P., Maass K., Seifert G., Steinhäuser C., Spray D.C., Scemes E. Cx43 Carboxyl Terminal Domain Determines AQP4 and Cx30 Endfoot Organization and Blood Brain Barrier Permeability. Sci. Rep. 2021;11:24334. doi: 10.1038/s41598-021-03694-x. PubMed DOI PMC

Kwon M.J., Shin H.Y., Cui Y., Kim H., Thi A.H.L., Choi J.Y., Kim E.Y., Hwang D.H., Kim B.G. CCL2 Mediates Neuron–Macrophage Interactions to Drive Proregenerative Macrophage Activation Following Preconditioning Injury. J. Neurosci. 2015;35:15934–15947. doi: 10.1523/JNEUROSCI.1924-15.2015. PubMed DOI PMC

Finneran D.J., Nash K.R. Neuroinflammation and Fractalkine Signaling in Alzheimer’s Disease. J. Neuroinflamm. 2019;16:30. doi: 10.1186/s12974-019-1412-9. PubMed DOI PMC

Angelopoulou E., Paudel Y.N., Shaikh M.F., Piperi C. Fractalkine (CX3CL1) Signaling and Neuroinflammation in Parkinson’s Disease: Potential Clinical and Therapeutic Implications. Pharmacol. Res. 2020;158:104930. doi: 10.1016/j.phrs.2020.104930. PubMed DOI

Herman F.J., Pasinetti G.M. Principles of Inflammasome Priming and Inhibition: Implications for Psychiatric Disorders. Brain Behav. Immun. 2018;73:66–84. doi: 10.1016/j.bbi.2018.06.010. PubMed DOI PMC

Fiebich B.L., Akter S., Akundi R.S. The Two-Hit Hypothesis for Neuroinflammation: Role of Exogenous ATP in Modulating Inflammation in the Brain. Front. Cell. Neurosci. 2014;8:260. doi: 10.3389/fncel.2014.00260. PubMed DOI PMC

Haroon E., Miller A.H., Sanacora G. Inflammation, Glutamate, and Glia: A Trio of Trouble in Mood Disorders. Neuropsychopharmacology. 2017;42:193–215. doi: 10.1038/npp.2016.199. PubMed DOI PMC

Culmsee C., Michels S., Scheu S., Arolt V., Dannlowski U., Alferink J. Mitochondria, Microglia, and the Immune System-How Are They Linked in Affective Disorders? Front. Psychiatry. 2018;9:739. doi: 10.3389/fpsyt.2018.00739. PubMed DOI PMC

Li W., Kui L., Demetrios T., Gong X., Tang M. A Glimmer of Hope: Maintain Mitochondrial Homeostasis to Mitigate Alzheimer’s Disease. Aging Dis. 2020;11:1260–1275. doi: 10.14336/AD.2020.0105. PubMed DOI PMC

Stoyanov S., Sun W., Düsedau H.P., Cangalaya C., Choi I., Mirzapourdelavar H., Baidoe-Ansah D., Kaushik R., Neumann J., Dunay I.R., et al. Attenuation of the Extracellular Matrix Restores Microglial Activity during the Early Stage of Amyloidosis. Glia. 2021;69:182–200. doi: 10.1002/glia.23894. PubMed DOI

Floden A.M., Combs C.K. Microglia Demonstrate Age-Dependent Interaction with Beta-Amyloid Fibrils. J. Alzheimers Dis. 2011;25:279–293. doi: 10.3233/JAD-2011-101014. PubMed DOI PMC

Von Bernhardi R., Eugenín-von Bernhardi L., Eugenín J. Microglial Cell Dysregulation in Brain Aging and Neurodegeneration. Front. Aging Neurosci. 2015;7:124. doi: 10.3389/fnagi.2015.00124. PubMed DOI PMC

Waller R., Baxter L., Fillingham D.J., Coelho S., Pozo J.M., Mozumder M., Frangi A.F., Ince P.G., Simpson J.E., Highley J.R. Iba-1−/CD68+ Microglia Are a Prominent Feature of Age-Associated Deep Subcortical White Matter Lesions. PLoS ONE. 2019;14:e0210888. doi: 10.1371/journal.pone.0210888. PubMed DOI PMC

Bennett F.C., Bennett M.L., Yaqoob F., Mulinyawe S.B., Grant G.A., Hayden Gephart M., Plowey E.D., Barres B.A. A Combination of Ontogeny and CNS Environment Establishes Microglial Identity. Neuron. 2018;98:1170–1183.e8. doi: 10.1016/j.neuron.2018.05.014. PubMed DOI PMC

Van der Poel M., Ulas T., Mizee M.R., Hsiao C.-C., Miedema S.S.M., Adelia, Schuurman K.G., Helder B., Tas S.W., Schultze J.L., et al. Transcriptional Profiling of Human Microglia Reveals Grey–White Matter Heterogeneity and Multiple Sclerosis-Associated Changes. Nat. Commun. 2019;10:1139. doi: 10.1038/s41467-019-08976-7. PubMed DOI PMC

Jha M.K., Jo M., Kim J.-H., Suk K. Microglia-Astrocyte Crosstalk: An Intimate Molecular Conversation. Neuroscientist. 2019;25:227–240. doi: 10.1177/1073858418783959. PubMed DOI

Bush T.G., Puvanachandra N., Horner C.H., Polito A., Ostenfeld T., Svendsen C.N., Mucke L., Johnson M.H., Sofroniew M.V. Leukocyte Infiltration, Neuronal Degeneration, and Neurite Outgrowth after Ablation of Scar-Forming, Reactive Astrocytes in Adult Transgenic Mice. Neuron. 1999;23:297–308. doi: 10.1016/S0896-6273(00)80781-3. PubMed DOI

Chi S., Cui Y., Wang H., Jiang J., Zhang T., Sun S., Zhou Z., Zhong Y., Xiao B. Astrocytic Piezo1-Mediated Mechanotransduction Determines Adult Neurogenesis and Cognitive Functions. Neuron. 2022;110:2984–2999.e8. doi: 10.1016/j.neuron.2022.07.010. PubMed DOI

Moeendarbary E., Weber I.P., Sheridan G.K., Koser D.E., Soleman S., Haenzi B., Bradbury E.J., Fawcett J., Franze K. The Soft Mechanical Signature of Glial Scars in the Central Nervous System. Nat. Commun. 2017;8:14787. doi: 10.1038/ncomms14787. PubMed DOI PMC

Haupt C., Witte O.W., Frahm C. Up-Regulation of Connexin43 in the Glial Scar Following Photothrombotic Ischemic Injury. Mol. Cell. Neurosci. 2007;35:89–99. doi: 10.1016/j.mcn.2007.02.005. PubMed DOI