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The role of glial autophagy in Alzheimer’s disease

Molecular Psychiatry volume 28, pages 4528–4539 (2023)Cite this article

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Abstract

Although Alzheimer’s disease is the most pervasive neurodegenerative disorder, the mechanism underlying its development is still not precisely understood. Available data indicate that pathophysiology of this disease may involve impaired autophagy in glial cells. The dysfunction is manifested as reduced ability of astrocytes and microglia to clear abnormal protein aggregates. Consequently, excessive accumulation of amyloid beta plaques and neurofibrillary tangles activates microglia and astrocytes leading to decreased number of mature myelinated oligodendrocytes and death of neurons. These pathologic effects of autophagy dysfunction can be rescued by pharmacological activation of autophagy. Therefore, a deeper understanding of the molecular mechanisms involved in autophagy dysfunction in glial cells in Alzheimer’s disease may lead to the development of new therapeutic strategies. However, such strategies need to take into consideration differences in regulation of autophagy in different types of neuroglia.

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Fig. 1: Three types of autophagy.
Fig. 2: Potential mechanisms linking APOE4 and the autophagy and mitophagy in astrocytes during Alzheimer’s Disease.
Fig. 3: Potential effect of autophagy on microglia morphology and polarization status.
Fig. 4: Schematic overview of the effect of amyloid plaques on autophagy in microglia.
Fig. 5: Schematic overview of the role of oligodendroglial autophagy in AD.
Fig. 6: Schematic summary of the relationship between disturbed autophagy in the glial cells with the progression of Alzheimer’s disease.

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References

  1. Wong W. Economic burden of Alzheimer disease and managed care considerations. Am J Manag Care. 2020;26:S177–83.

    PubMed  Google Scholar 

  2. Niikura T, Tajima H, Kita Y. Neuronal cell death in Alzheimers disease and a neuroprotective factor, humanin [Internet]. Curr Neuropharmacol. 2006;4:139–47. https://doi.org/10.2174/157015906776359577.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Canet G, Chevallier N, Zussy C, Desrumaux C, Givalois L. Central role of glucocorticoid receptors in Alzheimer’s disease and depression [Internet]. Front Neurosci. 2018;12:739. https://doi.org/10.3389/fnins.2018.00739. Available from

    Article  PubMed  PubMed Central  Google Scholar 

  4. Gu L, Guo Z. Alzheimer’s Aβ42 and Aβ40 peptides form interlaced amyloid fibrils. J Neurochem. 2013;126:305–11.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Glick D, Barth S, Macleod KF. Autophagy: cellular and molecular mechanisms. J Pathol. 2010;221:3–12.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Fakhoury M. Microglia and astrocytes in Alzheimer’s disease: implications for therapy. Curr Neuropharmacol. 2018;16:508–18.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Lorenzini L, Fernandez M, Baldassarro VA, Bighinati A, Giuliani A, Calzà L, et al. White matter and neuroprotection in Alzheimer’s dementia [Internet]. Molecules. 2020;25:503 https://doi.org/10.3390/molecules25030503.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. von Bartheld CS, Bahney J, Herculano-Houzel S. The search for true numbers of neurons and glial cells in the human brain: a review of 150 years of cell counting. J Comp Neurol. 2016;524:3865–95.

    Google Scholar 

  9. Papouin T, Dunphy J, Tolman M, Foley JC, Haydon PG. Astrocytic control of synaptic function. Philos Trans R Soc Lond B Biol Sci. 2017;372. Available from: https://doi.org/10.1098/rstb.2016.0154.

  10. Eide PK, Hasan-Olive MM, Hansson HA, Enger R. Increased occurrence of pathological mitochondria in astrocytic perivascular endfoot processes and neurons of idiopathic intracranial hypertension. J Neurosci Res. 2021;99:467–80.

    CAS  PubMed  Google Scholar 

  11. O’Leary LA, Mechawar N. Implication of cerebral astrocytes in major depression: a review of fine neuroanatomical evidence in humans. Glia 2021;69:2077–99.

    PubMed  Google Scholar 

  12. Mills WA 3rd, Woo AM, Jiang S, Martin J, Surendran D, Bergstresser M, et al. Astrocyte plasticity in mice ensures continued endfoot coverage of cerebral blood vessels following injury and declines with age. Nat Commun. 2022;13:1794.

    PubMed  PubMed Central  Google Scholar 

  13. Cabezas R, Avila-Rodriguez M, Vega-Vela NE, Echeverria V, González J, Hidalgo OA, et al. Growth factors and astrocytes metabolism: possible roles for platelet derived growth factor. Med Chem. 2016;12:204–10.

    CAS  PubMed  Google Scholar 

  14. Chen W, He B, Tong W, Zeng J, Zheng P. Astrocytic insulin-like growth factor-1 protects neurons against excitotoxicity. Front Cell Neurosci. 2019;13:298.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Litwiniuk A, Domańska A, Chmielowska M, Martyńska L, Bik W, Kalisz M. The effects of Alpha-Linolenic Acid on the secretory activity of astrocytes and amyloid-associated neurodegeneration in differentiated SH-SY5Y cells: Alpha-Linolenic Acid Protects the SH-SY5Y cells against Amyloid Toxicity. Oxid Med Cell Longev. 2020;2020:8908901.

    PubMed  PubMed Central  Google Scholar 

  16. Jiwaji Z, Hardingham GE. Good, bad, and neglectful: astrocyte changes in neurodegenerative disease. Free Radic Biol Med. 2022;182:93–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Norden DM, Fenn AM, Dugan A, Godbout JP. TGFβ produced by IL-10 redirected astrocytes attenuates microglial activation [Internet]. Glia. 2014;62:881–95. https://doi.org/10.1002/glia.22647.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Jha MK, Jo M, Kim JH, Suk K. Microglia-Astrocyte crosstalk: an intimate molecular conversation. Neuroscientist 2019;25:227–40.

    CAS  PubMed  Google Scholar 

  19. Molina-Gonzalez I, Holloway RK, Jiwaji Z, Dando O, Kent SA, Emelianova K, et al. Astrocyte-oligodendrocyte interaction regulates central nervous system regeneration. Nat Commun. 2023;14:3372.

  20. Nutma E, van Gent D, Amor S, Peferoen LAN Astrocyte and Oligodendrocyte Cross-Talk in the Central Nervous System. Cells. 2020;9. Available from: https://doi.org/10.3390/cells9030600.

  21. Niu J, Tsai HH, Hoi KK, Huang N, Yu G, Kim K, et al. Aberrant oligodendroglial-vascular interactions disrupt the blood-brain barrier, triggering CNS inflammation. Nat Neurosci. 2019;22:709–18.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Ha S, Jeong SH, Yi K, Chu JJM, Kim S, Kim EK, et al. Autophagy mediates astrogenesis in adult hippocampal neural stem cells. Exp Neurobiol. 2019;28:229–46.

    PubMed  PubMed Central  Google Scholar 

  23. Wang S, Li B, Qiao H, Lv X, Liang Q, Shi Z, et al. Autophagy-related gene Atg5 is essential for astrocyte differentiation in the developing mouse cortex. EMBO Rep. 2014;15:1053–61.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Chandrasekaran A, Dittlau KS, Corsi GI, Haukedal H, Doncheva NT, Ramakrishna S, et al. Astrocytic reactivity triggered by defective autophagy and metabolic failure causes neurotoxicity in frontotemporal dementia type 3. Stem Cell Rep. 2021;16:2736–51.

    CAS  Google Scholar 

  25. Motori E, Puyal J, Toni N, Ghanem A, Angeloni C, Malaguti M, et al. Inflammation-induced alteration of astrocyte mitochondrial dynamics requires autophagy for mitochondrial network maintenance. Cell Metab. 2013;18:844–59.

    CAS  PubMed  Google Scholar 

  26. Herdy JR, Traxler L, Agarwal RK, Karbacher L, Schlachetzki JCM, Boehnke L, et al. Increased post-mitotic senescence in aged human neurons is a pathological feature of Alzheimer’s disease. Cell Stem Cell. 2022;29:1637–52.e6.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Beltran-Lobo P, Reid MJ, Jimenez-Sanchez M, Verkhratsky A, Perez-Nievas BG, Noble W. Astrocyte adaptation in Alzheimer’s disease: a focus on astrocytic P2X7R. Essays Biochem. 2022; Available from: https://doi.org/10.1042/EBC20220079.

  28. Zamanian JL, Xu L, Foo LC, Nouri N, Zhou L, Giffard RG, et al. Genomic analysis of reactive astrogliosis. J Neurosci. 2012;32:6391–410.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Khodadadei F, Arshad R, Morales DM, Gluski J, Marupudi NI, McAllister JP 2nd, et al. The effect of A1 and A2 reactive astrocyte expression on hydrocephalus shunt failure. Fluids Barriers CNS. 2022;19:78.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Narayan P, Holmström KM, Kim DH, Whitcomb DJ, Wilson MR, St George-Hyslop P, et al. Rare individual amyloid-β oligomers act on astrocytes to initiate neuronal damage. Biochemistry. 2014;53:2442–53.

    CAS  PubMed  Google Scholar 

  31. González-Reyes RE, Nava-Mesa MO, 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.

    PubMed  PubMed Central  Google Scholar 

  32. Beard E, Lengacher S, Dias S, Magistretti PJ, Finsterwald C. Astrocytes as key regulators of brain energy metabolism: new therapeutic perspectives. Front Physiol. 2021;12:825816.

    PubMed  Google Scholar 

  33. Park JS, Kam TI, Lee S, Park H, Oh Y, Kwon SH, et al. Blocking microglial activation of reactive astrocytes is neuroprotective in models of Alzheimer’s disease. Acta Neuropathol Commun. 2021;9:78.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Di Benedetto G, Burgaletto C, Bellanca CM, Munafò A, Bernardini R, Cantarella G. Role of Microglia and Astrocytes in Alzheimer’s Disease: From Neuroinflammation to Ca Homeostasis Dysregulation. Cells. 2022;11. Available from: https://doi.org/10.3390/cells11172728.

  35. Singh D. Astrocytic and microglial cells as the modulators of neuroinflammation in Alzheimer’s disease. J Neuroinflamm. 2022;19:206.

    CAS  Google Scholar 

  36. He M, Dong H, Huang Y, Lu S, Zhang S, Qian Y, et al. Astrocyte-Derived CCL2 is associated with M1 activation and recruitment of cultured microglial cells. Cell Physiol Biochem. 2016;38:859–70.

    CAS  PubMed  Google Scholar 

  37. Park J, Wetzel I, Marriott I, Dréau D, D’Avanzo C, Kim DY, et al. A 3D human triculture system modeling neurodegeneration and neuroinflammation in Alzheimer’s disease. Nat Neurosci. 2018;21:941–51.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Norden DM, Trojanowski PJ, Walker FR, Godbout JP. Insensitivity of astrocytes to interleukin 10 signaling following peripheral immune challenge results in prolonged microglial activation in the aged brain. Neurobiol Aging. 2016;44:22–41.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Nixon RA, Wegiel J, Kumar A, Yu WH, Peterhoff C, Cataldo A, et al. Extensive involvement of autophagy in Alzheimer disease: an immuno-electron microscopy study. J Neuropathol Exp Neurol. 2005;64:113–22.

    PubMed  Google Scholar 

  40. Pickford F, Masliah E, Britschgi M, Lucin K, Narasimhan R, Jaeger PA, et al. The autophagy-related protein beclin 1 shows reduced expression in early Alzheimer disease and regulates amyloid beta accumulation in mice. J Clin Investig. 2008;118:2190–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Shin JY, Park HJ, Kim HN, Oh SH, Bae JS, Ha HJ, et al. Mesenchymal stem cells enhance autophagy and increase β-amyloid clearance in Alzheimer disease models. Autophagy. 2014;10:32–44.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Shi Y, Yamada K, Liddelow SA, Smith ST, Zhao L, Luo W, et al. ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy. Nature. 2017;549:523–7.

    PubMed  PubMed Central  Google Scholar 

  43. Simonovitch S, Schmukler E, Bespalko A, Iram T, Frenkel D, Holtzman DM, et al. Impaired Autophagy in APOE4 Astrocytes. J Alzheimers Dis. 2016;51:915–27.

    CAS  PubMed  Google Scholar 

  44. Fote GM, Geller NR, Efstathiou NE, Hendricks N, Vavvas DG, Reidling JC, et al. Isoform-dependent lysosomal degradation and internalization of apolipoprotein E requires autophagy proteins. J Cell Sci. 2022;135. Available from: https://doi.org/10.1242/jcs.258687.

  45. Yamazaki Y, Zhao N, Caulfield TR, Liu CC, Bu G. Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies. Nat Rev Neurol. 2019;15:501–18.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Zhao J, Davis MD, Martens YA, Shinohara M, Graff-Radford NR, Younkin SG, et al. APOE ε4/ε4 diminishes neurotrophic function of human iPSC-derived astrocytes. Hum Mol Genet. 2017;26:2690–700.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Ries M, Sastre M. Mechanisms of Aβ clearance and degradation by Glial cells. Front Aging Neurosci. 2016;8:160.

    PubMed  PubMed Central  Google Scholar 

  48. Gomez-Arboledas A, Davila JC, Sanchez-Mejias E, Navarro V, Nuñez-Diaz C, Sanchez-Varo R, et al. Phagocytic clearance of presynaptic dystrophies by reactive astrocytes in Alzheimer’s disease. Glia. 2018;66:637–53.

    PubMed  Google Scholar 

  49. Mahan TE, Wang C, Bao X, Choudhury A, Ulrich JD, Holtzman DM. Selective reduction of astrocyte apoE3 and apoE4 strongly reduces Aβ accumulation and plaque-related pathology in a mouse model of amyloidosis. Mol Neurodegener. 2022;17:13.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Parcon PA, Balasubramaniam M, Ayyadevara S, Jones RA, Liu L, Shmookler Reis RJ, et al. Apolipoprotein E4 inhibits autophagy gene products through direct, specific binding to CLEAR motifs. Alzheimers Dement. 2018;14:230–42.

    PubMed  Google Scholar 

  51. Napolitano G, Ballabio A. TFEB at a glance. J Cell Sci. 2016;129:2475–81.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Zhang YD, Zhao JJ. TFEB Participates in the Aβ-Induced pathogenesis of Alzheimer’s disease by regulating the autophagy-Lysosome pathway. DNA Cell Biol. 2015;34:661–8.

    CAS  PubMed  Google Scholar 

  53. Xiao Q, Yan P, Ma X, Liu H, Perez R, Zhu A, et al. Neuronal-Targeted TFEB Accelerates Lysosomal Degradation of APP, reducing Aβ generation and amyloid plaque pathogenesis. J Neurosci. 2015;35:12137–51.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Yang C, Su C, Iyaswamy A, Krishnamoorthi SK, Zhu Z, Yang S, et al. Celastrol enhances transcription factor EB (TFEB)-mediated autophagy and mitigates Tau pathology: implications for Alzheimer’s disease therapy. Acta Pharm Sin B. 2022;12:1707–22.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Sohn HY, Kim SI, Park JY, Park SH, Koh YH, Kim J, et al. ApoE4 attenuates autophagy via FoxO3a repression in the brain. Sci Rep. 2021;11:17604.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Du S, Jin F, Maneix L, Gedam M, Xu Y, Catic A, et al. FoxO3 deficiency in cortical astrocytes leads to impaired lipid metabolism and aggravated amyloid pathology. Aging Cell. 2021;20:e13432.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Söllvander S, Nikitidou E, Brolin R, Söderberg L, Sehlin D, Lannfelt L, et al. Accumulation of amyloid-β by astrocytes result in enlarged endosomes and microvesicle-induced apoptosis of neurons. Mol Neurodegener. 2016;11:38.

    PubMed  PubMed Central  Google Scholar 

  58. Lööv C, Mitchell CH, Simonsson M, Erlandsson A. Slow degradation in phagocytic astrocytes can be enhanced by lysosomal acidification. Glia. 2015;63:1997–2009.

    PubMed  PubMed Central  Google Scholar 

  59. Zhou Z, Bai J, Zhong S, Zhang R, Kang K, Zhang X, et al. Downregulation of ATP6V1A Involved in Alzheimer’s disease via synaptic vesicle cycle, phagosome, and oxidative phosphorylation. Oxid Med Cell Longev. 2021;2021:5555634.

    PubMed  PubMed Central  Google Scholar 

  60. Yambire KF, Rostosky C, Watanabe T, Pacheu-Grau D, Torres-Odio S, Sanchez-Guerrero A, et al. Impaired lysosomal acidification triggers iron deficiency and inflammation in vivo. Elife. 2019;8. Available from: https://doi.org/10.7554/eLife.51031.

  61. Huang YC, Hsu SM, Shie FS, Shiao YJ, Chao LJ, Chen HW, et al. Reduced mitochondria membrane potential and lysosomal acidification are associated with decreased oligomeric Aβ degradation induced by hyperglycemia: a study of mixed glia cultures. PLoS One. 2022;17:e0260966.

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Kim HN, Seo BR, Kim H, Koh JY. Cilostazol restores autophagy flux in bafilomycin A1-treated, cultured cortical astrocytes through lysosomal reacidification: roles of PKA, zinc and metallothionein 3. Sci Rep. 2020;10:9175.

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Lee H, Koh JY. Roles for H /K -ATPase and zinc transporter 3 in cAMP-mediated lysosomal acidification in bafilomycin A1-treated astrocytes. Glia. 2021;69:1110–25.

    CAS  PubMed  Google Scholar 

  64. Raha S, Ghosh A, Dutta D, Patel DR, Pahan K. Activation of PPARα enhances astroglial uptake and degradation of β-amyloid. Sci Signal. 2021;14:eabg4747.

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Abramov AY, Canevari L, Duchen MR. Beta-amyloid peptides induce mitochondrial dysfunction and oxidative stress in astrocytes and death of neurons through activation of NADPH oxidase. J Neurosci. 2004;24:565–75.

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Schmukler E, Solomon S, Simonovitch S, Goldshmit Y, Wolfson E, Michaelson DM, et al. Altered mitochondrial dynamics and function in APOE4-expressing astrocytes. Cell Death Dis. 2020;11:578.

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Palikaras K, Lionaki E, Tavernarakis N. Mechanisms of mitophagy in cellular homeostasis, physiology and pathology. Nat Cell Biol. 2018;20:1013–22.

    CAS  PubMed  Google Scholar 

  68. Iorio R, Celenza G, Petricca S. Mitophagy: molecular mechanisms, new concepts on parkin activation and the emerging role of AMPK/ULK1 Axis. Cells. 2021;11. Available from: https://doi.org/10.3390/cells11010030.

  69. Gkikas I, Palikaras K, Tavernarakis N. The role of mitophagy in innate immunity. Front Immunol. 2018;9:1283.

    PubMed  PubMed Central  Google Scholar 

  70. Lampinen R, Belaya I, Saveleva L, Liddell JR, Rait D, Huuskonen MT, et al. Neuron-astrocyte transmitophagy is altered in Alzheimer’s disease. Neurobiol Dis. 2022;170:105753.

    CAS  PubMed  Google Scholar 

  71. Franco-Bocanegra DK, Gourari Y, McAuley C, Chatelet DS, Johnston DA, Nicoll JAR, et al. Microglial morphology in Alzheimer’s disease and after Aβ immunotherapy. Sci Rep. 2021;11:15955.

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Arnold T, Betsholtz C. The importance of microglia in the development of the vasculature in the central nervous system. Vol. 5, Vasc Cell. 2013. p. 4. Available from: https://doi.org/10.1186/2045-824x-5-4.

  73. Borst K, Dumas AA, Prinz M. Microglia: immune and non-immune functions. Immunity. 2021;54:2194–208.

    CAS  PubMed  Google Scholar 

  74. Kalafatakis I, Karagogeos D. Oligodendrocytes and microglia: key players in myelin development, damage and repair. Biomolecules. 2021;11. Available from: https://doi.org/10.3390/biom11071058.

  75. Prinz M, Jung S, Priller J. Microglia biology: one century of evolving concepts. Cell. 2019;179:292–311.

    CAS  PubMed  Google Scholar 

  76. Lopes K, de P, Snijders GJL, Humphrey J, Allan A, Sneeboer MAM, et al. Genetic analysis of the human microglial transcriptome across brain regions, aging and disease pathologies. Nat Genet. 2022;54:4–17.

    CAS  PubMed  Google Scholar 

  77. Réu P, Khosravi A, Bernard S, Mold JE, Salehpour M, Alkass K, et al. The lifespan and turnover of microglia in the human brain. Cell Rep. 2017;20:779–84.

    PubMed  PubMed Central  Google Scholar 

  78. Jordão MJC, Sankowski R, Brendecke SM, Sagar, Locatelli G, Tai YH, et al. Single-cell profiling identifies myeloid cell subsets with distinct fates during neuroinflammation. Science. 2019;363. Available from: https://doi.org/10.1126/science.aat7554.

  79. Guo S, Wang H, Yin Y. Microglia polarization from M1 to M2 in neurodegenerative diseases. Front Aging Neurosci. 2022;14:815347.

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Xu Y, Propson NE, Du S, Xiong W, Zheng H. Autophagy deficiency modulates microglial lipid homeostasis and aggravates tau pathology and spreading. Proc Natl Acad Sci USA [Internet]. 2021;118. Available from: https://doi.org/10.1073/pnas.2023418118.

  81. Berglund R, Guerreiro-Cacais AO, Adzemovic MZ, Zeitelhofer M, Lund H, Ewing E, et al. Microglial autophagy-associated phagocytosis is essential for recovery from neuroinflammation. Sci Immunol. 2020;5. Available from: https://doi.org/10.1126/sciimmunol.abb5077.

  82. Jin MM, Wang F, Qi D, Liu WW, Gu C, Mao CJ, et al. A critical role of autophagy in regulating microglia polarization in neurodegeneration. Front Aging Neurosci. 2018;10:378.

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Cheng J, Liao Y, Dong Y, Hu H, Yang N, Kong X, et al. Microglial autophagy defect causes parkinson disease-like symptoms by accelerating inflammasome activation in mice. Autophagy. 2020;16:2193–205.

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Alam MM, Zhao XF, Liao Y, Mathur R, McCallum SE, Mazurkiewicz JE, et al. Deficiency of microglial autophagy increases the density of oligodendrocytes and susceptibility to severe forms of Seizures. eNeuro [Internet]. 2021;8. Available from: https://doi.org/10.1523/ENEURO.0183-20.2021.

  85. Hansen DV, Hanson JE, Sheng M. Microglia in Alzheimer’s disease. J Cell Biol. 2018;217:459–72.

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Kiani Shabestari S, Morabito S, Danhash EP, McQuade A, Sanchez JR, Miyoshi E, et al. Absence of microglia promotes diverse pathologies and early lethality in Alzheimer’s disease mice. Cell Rep. 2022;39:110961.

    CAS  PubMed  Google Scholar 

  87. Bolmont T, Haiss F, Eicke D, Radde R, Mathis CA, Klunk WE, et al. Dynamics of the microglial/amyloid interaction indicate a role in plaque maintenance. J Neurosci. 2008;28:4283–92.

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Tajbakhsh A, Read M, Barreto GE, Ávila-Rodriguez M, Gheibi-Hayat SM, Sahebkar A. Apoptotic neurons and amyloid-beta clearance by phagocytosis in Alzheimer’s disease: pathological mechanisms and therapeutic outlooks. Eur J Pharm. 2021;895:173873.

    CAS  Google Scholar 

  89. Lee JW, Nam H, Kim LE, Jeon Y, Min H, Ha S, et al. TLR4 (toll-like receptor 4) activation suppresses autophagy through inhibition of FOXO3 and impairs phagocytic capacity of microglia. Autophagy. 2019;15:753–70.

    CAS  PubMed  Google Scholar 

  90. Keren-Shaul H, Spinrad A, Weiner A, Matcovitch-Natan O, Dvir-Szternfeld R, Ulland TK, et al. A unique microglia type associated with restricting development of Alzheimer’s disease [Internet]. Cell. 2017;169:1276–90.e17. https://doi.org/10.1016/j.cell.2017.05.018.

    Article  CAS  PubMed  Google Scholar 

  91. Pomilio C, Gorojod RM, Riudavets M, Vinuesa A, Presa J, Gregosa A, et al. Microglial autophagy is impaired by prolonged exposure to β-amyloid peptides: evidence from experimental models and Alzheimer’s disease patients. Geroscience. 2020;42:613–32.

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Estfanous S, Daily KP, Eltobgy M, Deems NP, Anne MNK, Krause K, et al. Elevated Expression of MiR-17 in Microglia of Alzheimer’s disease patients abrogates autophagy-mediated Amyloid-β degradation. Front Immunol. 2021;12:705581.

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Spilman P, Podlutskaya N, Hart MJ, Debnath J, Gorostiza O, Bredesen D, et al. Inhibition of mTOR by Rapamycin Abolishes cognitive deficits and reduces Amyloid-β Levels in a Mouse Model of Alzheimer’s Disease [Internet]. PLoS One. 2010;5:e9979. https://doi.org/10.1371/journal.pone.0009979.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Lu J, Zhou W, Dou F, Wang C, Yu Z. TRPV1 sustains microglial metabolic reprogramming in Alzheimer’s disease. EMBO Rep. 2021;22:e52013.

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Fairley LH, Wong JH, Barron AM. Mitochondrial regulation of microglial immunometabolism in Alzheimer’s disease. Front Immunol. 2021;12:624538.

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Fang EF, Hou Y, Palikaras K, Adriaanse BA, Kerr JS, Yang B, et al. Mitophagy inhibits amyloid-β and tau pathology and reverses cognitive deficits in models of Alzheimer’s disease. Nat Neurosci. 2019;22:401–12.

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Fünfschilling U, Supplie LM, Mahad D, Boretius S, Saab AS, Edgar J, et al. Glycolytic oligodendrocytes maintain myelin and long-term axonal integrity. Nature. 2012;485:517–21.

    PubMed  PubMed Central  Google Scholar 

  98. Edgar JM, McLaughlin M, Yool D, Zhang SC, Fowler JH, Montague P, et al. Oligodendroglial modulation of fast axonal transport in a mouse model of hereditary spastic paraplegia. J Cell Biol. 2004;166:121–31.

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Akay LA, Effenberger AH, Tsai LH. Cell of all trades: oligodendrocyte precursor cells in synaptic, vascular, and immune function. Genes Dev. 2021;35:180–98.

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Juurlink BH, Thorburne SK, Hertz L. Peroxide-scavenging deficit underlies oligodendrocyte susceptibility to oxidative stress. Glia. 1998;22:371–8.

    CAS  PubMed  Google Scholar 

  101. Chavda V, Singh K, Patel V, Mishra M, Mishra AK. Neuronal glial crosstalk: specific and shared mechanisms in Alzheimer’s disease. Brain Sci. 2022;12. Available from: https://doi.org/10.3390/brainsci12010075.

  102. Dulamea AO. Role of Oligodendrocyte dysfunction in demyelination, remyelination and neurodegeneration in multiple sclerosis. Adv Exp Med Biol. 2017;958:91–127.

    CAS  PubMed  Google Scholar 

  103. Misrielal C, Mauthe M, Reggiori F, Eggen BJL. Autophagy in multiple sclerosis: two sides of the same coin. Front Cell Neurosci. 2020;14:603710.

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Flygt J, Gumucio A, Ingelsson M, Skoglund K, Holm J, Alafuzoff I, et al. Human traumatic brain injury results in oligodendrocyte death and increases the number of oligodendrocyte progenitor cells. J Neuropathol Exp Neurol. 2016;75:503–15.

    CAS  PubMed  Google Scholar 

  105. Zhang L, Wang H. Autophagy in traumatic brain injury: a new target for therapeutic intervention. Front Mol Neurosci. 2018;11:190.

    PubMed  PubMed Central  Google Scholar 

  106. Aber ER, Griffey CJ, Davies T, Li AM, Yang YJ, Croce KR, et al. Oligodendroglial macroautophagy is essential for myelin sheath turnover to prevent neurodegeneration and death. Cell Rep. 2022;41:111480.

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Smith CM, Mayer JA, Duncan ID. Autophagy promotes oligodendrocyte survival and function following dysmyelination in a long-lived myelin mutant [Internet]. J Neurosci. 2013;33:8088–100. https://doi.org/10.1523/jneurosci.0233-13.2013.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Bankston AN, Forston MD, Howard RM, Andres KR, Smith AE, Ohri SS, et al. Autophagy is essential for oligodendrocyte differentiation, survival, and proper myelination. Glia. 2019;67:1745–59.

    PubMed  Google Scholar 

  109. Papuć E, Rejdak K. The role of myelin damage in Alzheimer’s disease pathology [Internet]. Arch Med Sci. 2020;16:345–341. https://doi.org/10.5114/aoms.2018.76863.

    Article  CAS  PubMed  Google Scholar 

  110. Collins-Praino LE, Francis YI, Griffith EY, Wiegman AF, Urbach J, Lawton A, et al. Soluble amyloid beta levels are elevated in the white matter of Alzheimer’s patients, independent of cortical plaque severity [Internet]. Vol. 2, Acta Neuropathol Commun. 2014. Available from: https://doi.org/10.1186/s40478-014-0083-0.

  111. Lee JT, Xu J, Lee JM, Ku G, Han X, Yang DI, et al. Amyloid-beta peptide induces oligodendrocyte death by activating the neutral sphingomyelinase-ceramide pathway. J Cell Biol. 2004;164:123–31.

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Xu J, Chen S, Ahmed SH, Chen H, Ku G, Goldberg MP, et al. Amyloid-beta peptides are cytotoxic to oligodendrocytes. J Neurosci. 2001;21:RC118.

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Kaya I, Jennische E, Lange S, Tarik Baykal A, Malmberg P, Fletcher JS. Brain region-specific amyloid plaque-associated myelin lipid loss, APOE deposition and disruption of the myelin sheath in familial Alzheimer’s disease mice. J Neurochem. 2020;154:84–98.

    CAS  PubMed  Google Scholar 

  114. Pak K, Chan SL, Mattson MP. Presenilin-1 mutation sensitizes oligodendrocytes to glutamate and amyloid toxicities, and exacerbates white matter damage and memory impairment in mice. Neuromol Med. 2003;3:53–64.

    CAS  Google Scholar 

  115. Ferreira S, Pitman KA, Wang S, Summers BS, Bye N, Young KM, et al. Amyloidosis is associated with thicker myelin and increased oligodendrogenesis in the adult mouse brain. J Neurosci Res. 2020;98:1905–32.

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Quintela-López T, Ortiz-Sanz C, Serrano-Regal MP, Gaminde-Blasco A, Valero J, Baleriola J, et al. Aβ oligomers promote oligodendrocyte differentiation and maturation via integrin β1 and Fyn kinase signaling. Cell Death Dis. 2019;10:445.

    PubMed  PubMed Central  Google Scholar 

  117. Ossola B, Zhao C, Compston A, Pluchino S, Franklin RJM, Spillantini MG. Neuronal expression of pathological tau accelerates oligodendrocyte progenitor cell differentiation. Glia. 2016;64:457–71.

    PubMed  Google Scholar 

  118. Chacon-De-La-Rocha I, Fryatt G, Rivera AD, Verkhratsky A, Raineteau O, Gomez-Nicola D, et al. Accelerated Dystrophy and Decay of Oligodendrocyte Precursor Cells in the APP/PS1 Model of Alzheimer’s-Like Pathology. Front Cell Neurosci. 2020;14:575082.

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Vanzulli I, Papanikolaou M, De-La-Rocha IC, Pieropan F, Rivera AD, Gomez-Nicola D, et al. Disruption of oligodendrocyte progenitor cells is an early sign of pathology in the triple transgenic mouse model of Alzheimer’s disease. Neurobiol Aging. 2020;94:130–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Zhang P, Kishimoto Y, Grammatikakis I, Gottimukkala K, Cutler RG, Zhang S, et al. Senolytic therapy alleviates Aβ-associated oligodendrocyte progenitor cell senescence and cognitive deficits in an Alzheimer’s disease model [Internet]. Nat Neurosci. 2019;22:719–28. https://doi.org/10.1038/s41593-019-0372-9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Li W, Tang Y, Fan Z, Meng Y, Yang G, Luo J, et al. Autophagy is involved in oligodendroglial precursor-mediated clearance of amyloid peptide. Mol Neurodegener. 2013;8:27.

    PubMed  PubMed Central  Google Scholar 

  122. Ktena N, Kaplanis SI, Kolotuev I, Georgilis A, Kallergi E, Stavroulaki V, et al. Autophagic degradation of CNS myelin maintains axon integrity. Cell Stress Chaperones. 2022;6:93–107.

    CAS  Google Scholar 

  123. Saraswat Ohri S, Bankston AN, Mullins SA, Liu Y, Andres KR, Beare JE, et al. Blocking autophagy in oligodendrocytes limits functional recovery after spinal cord injury. J Neurosci. 2018;38:5900–12.

    PubMed  PubMed Central  Google Scholar 

  124. Wang MR, Zhang XJ, Liu HC, Ma WD, Zhang ML, Zhang Y, et al. Matrine protects oligodendrocytes by inhibiting their apoptosis and enhancing mitochondrial autophagy. Brain Res Bull. 2019;153:30–8.

    CAS  PubMed  Google Scholar 

  125. Fernandes MGF, Luo JXX, Cui QL, Perlman K, Pernin F, Yaqubi M, et al. Age-related injury responses of human oligodendrocytes to metabolic insults: link to BCL-2 and autophagy pathways. Commun Biol. 2021;4:20.

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Karlsson M, Zhang C, Méar L, Zhong W, Digre A, Katona B, et al. A single-cell type transcriptomics map of human tissues. Sci Adv. 2021;7. Available from: https://doi.org/10.1126/sciadv.abh2169.

  127. Zhang Y, Chen K, Sloan SA, Bennett ML, Scholze AR, O’Keeffe S, et al. An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex. J Neurosci. 2014;34:11929–47.

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Eskelinen EL, Illert AL, Tanaka Y, Schwarzmann G, Blanz J, Von Figura K, et al. Role of LAMP-2 in lysosome biogenesis and autophagy. Mol Biol Cell. 2002;13:3355–68.

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Lundquist MR, Goncalves MD, Loughran RM, Possik E, Vijayaraghavan T, Yang A, et al. Phosphatidylinositol-5-Phosphate 4-Kinases Regulate Cellular Lipid Metabolism By Facilitating Autophagy. Mol Cell. 2018;70:531–44.e9.

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Noori A, Mezlini AM, Hyman BT, Serrano-Pozo A, Das S. Systematic review and meta-analysis of human transcriptomics reveals neuroinflammation, deficient energy metabolism, and proteostasis failure across neurodegeneration. Neurobiol Dis. 2021;149:105225.

    CAS  PubMed  Google Scholar 

  131. Festa BP, Siddiqi FH, Jimenez-Sanchez M, Won H, Rob M, Djajadikerta A, et al. Microglial-to-neuronal CCR5 signaling regulates autophagy in neurodegeneration. Neuron. 2023;111:2021–37.e12.

    CAS  PubMed  Google Scholar 

  132. Guo F, Liu X, Cai H, Le W. Autophagy in neurodegenerative diseases: pathogenesis and therapy. Brain Pathol. 2018;28:3–13.

    CAS  PubMed  Google Scholar 

  133. Frake RA, Ricketts T, Menzies FM, Rubinsztein DC. Autophagy and neurodegeneration. J Clin Investig. 2015;125:65–74.

    PubMed  PubMed Central  Google Scholar 

  134. Bussi C, Peralta Ramos JM, Arroyo DS, Gallea JI, Ronchi P, Kolovou A, et al. Alpha-synuclein fibrils recruit TBK1 and OPTN to lysosomal damage sites and induce autophagy in microglial cells. J Cell Sci [Internet]. 2018;131. Available from: https://doi.org/10.1242/jcs.226241.

  135. Fujikake N, Shin M, Shimizu S. Association between autophagy and neurodegenerative diseases. Front Neurosci. 2018;12:255.

    PubMed  PubMed Central  Google Scholar 

  136. Fernández-Pajarín G, Sesar A, Ares-Pensado B, Castro A. Parkinson’s disease secondary to 2 mutations of genes involved in lysosomal protein degradation. Neurol (Engl Ed). 2020;35:611–2.

    Google Scholar 

  137. Martin DDO, Ladha S, Ehrnhoefer DE, Hayden MR. Autophagy in Huntington disease and huntingtin in autophagy. Trends Neurosci. 2015;38:26–35.

    CAS  PubMed  Google Scholar 

  138. Rudnick ND, Griffey CJ, Guarnieri P, Gerbino V, Wang X, Piersaint JA, et al. Distinct roles for motor neuron autophagy early and late in the SOD1 mouse model of ALS. Proc Natl Acad Sci USA. 2017;114:E8294–303.

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Yilmaz R, Müller K, Brenner D, Volk AE, Borck G, Hermann A, et al. SQSTM1/p62 variants in 486 patients with familial ALS from Germany and Sweden. Neurobiol Aging. 2020;87:139.e9–139.e15.

    CAS  PubMed  Google Scholar 

  140. Braak H, Sastre M, Del Tredici K. Development of alpha-synuclein immunoreactive astrocytes in the forebrain parallels stages of intraneuronal pathology in sporadic Parkinson’s disease. Acta Neuropathol. 2007;114:231–41.

    CAS  PubMed  Google Scholar 

  141. Lindström V, Gustafsson G, Sanders LH, Howlett EH, Sigvardson J, Kasrayan A, et al. Extensive uptake of α-synuclein oligomers in astrocytes results in sustained intracellular deposits and mitochondrial damage. Mol Cell Neurosci. 2017;82:143–56.

    PubMed  Google Scholar 

  142. Jewett M, Dickson E, Brolin K, Negrini M, Jimenez-Ferrer I, Swanberg M. Glutathione -Transferase Alpha 4 Prevents Dopamine Neurodegeneration in a Rat Alpha-Synuclein Model of Parkinson’s Disease. Front Neurol. 2018;9:222.

    PubMed  PubMed Central  Google Scholar 

  143. Angot E, Steiner JA, Lema Tomé CM, Ekström P, Mattsson B, Björklund A, et al. Alpha-synuclein cell-to-cell transfer and seeding in grafted dopaminergic neurons in vivo. PLoS One. 2012;7:e39465.

    CAS  PubMed  PubMed Central  Google Scholar 

  144. Chavarría C, Rodríguez-Bottero S, Quijano C, Cassina P, Souza JM. Impact of monomeric, oligomeric and fibrillar alpha-synuclein on astrocyte reactivity and toxicity to neurons. Biochem J. 2018;475:3153–69.

    PubMed  Google Scholar 

  145. Lu SZ, Guo YS, Liang PZ, Zhang SZ, Yin S, Yin YQ, et al. Suppression of astrocytic autophagy by αB-crystallin contributes to α-synuclein inclusion formation. Transl Neurodegener. 2019;8:3.

    PubMed  PubMed Central  Google Scholar 

  146. Erustes AG, Stefani FY, Terashima JY, Stilhano RS, Monteforte PT, da Silva Pereira GJ, et al. Overexpression of α-synuclein in an astrocyte cell line promotes autophagy inhibition and apoptosis. J Neurosci Res. 2018;96:160–71.

    CAS  PubMed  Google Scholar 

  147. Qiao C, Yin N, Gu HY, Zhu JL, Ding JH, Lu M, et al. Atp13a2 Deficiency Aggravates Astrocyte-Mediated Neuroinflammation via NLRP3 Inflammasome Activation. CNS Neurosci Ther. 2016;22:451–60.

    CAS  PubMed  PubMed Central  Google Scholar 

  148. Booth HDE, Hirst WD, Wade-Martins R. The role of astrocyte dysfunction in parkinson’s disease pathogenesis. Trends Neurosci. 2017;40:358–70.

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Qin Y, Qiu J, Wang P, Liu J, Zhao Y, Jiang F, et al. Impaired autophagy in microglia aggravates dopaminergic neurodegeneration by regulating NLRP3 inflammasome activation in experimental models of Parkinson’s disease. Brain Behav Immun. 2021;91:324–38.

    CAS  PubMed  Google Scholar 

  150. Tu HY, Yuan BS, Hou XO, Zhang XJ, Pei CS, Ma YT, et al. α-synuclein suppresses microglial autophagy and promotes neurodegeneration in a mouse model of Parkinson’s disease. Aging Cell. 2021;20:e13522.

    CAS  PubMed  PubMed Central  Google Scholar 

  151. Choi I, Zhang Y, Seegobin SP, Pruvost M, Wang Q, Purtell K, et al. Microglia clear neuron-released α-synuclein via selective autophagy and prevent neurodegeneration. Nat Commun. 2020;11:1386.

    CAS  PubMed  PubMed Central  Google Scholar 

  152. Rocha SM, Kirkley KS, Chatterjee D, Aboellail TA, Smeyne RJ, Tjalkens RB. Microglia-specific knock-out of NF-κB/IKK2 increases the accumulation of misfolded α-synuclein through the inhibition of p62/sequestosome-1-dependent autophagy in the rotenone model of Parkinson’s disease. Glia. 2023;71:2154–79.

    CAS  PubMed  Google Scholar 

  153. Pukass K, Richter-Landsberg C. Oxidative stress promotes uptake, accumulation, and oligomerization of extracellular α-synuclein in oligodendrocytes. J Mol Neurosci. 2014;52:339–52.

    CAS  PubMed  Google Scholar 

  154. Pukaß K, Goldbaum O, Richter-Landsberg C. Mitochondrial impairment and oxidative stress compromise autophagosomal degradation of α-synuclein in oligodendroglial cells. J Neurochem. 2015;135:194–205.

    PubMed  Google Scholar 

  155. Kaji S, Maki T, Kinoshita H, Uemura N, Ayaki T, Kawamoto Y, et al. Pathological Endogenous α-Synuclein Accumulation in Oligodendrocyte Precursor Cells Potentially Induces Inclusions in Multiple System Atrophy. Stem Cell Rep. 2018;10:356–65.

    CAS  Google Scholar 

  156. Mavroeidi P, Arvanitaki F, Vetsi M, Becker S, Vlachakis D, Jensen PH, et al. Autophagy mediates the clearance of oligodendroglial SNCA/alpha-synuclein and TPPP/p25A in multiple system atrophy models. Autophagy. 2022;18:2104–33.

    CAS  PubMed  PubMed Central  Google Scholar 

  157. Wilton DK, Stevens B. The contribution of glial cells to Huntington’s disease pathogenesis. Neurobiol Dis. 2020;143:104963.

    PubMed  PubMed Central  Google Scholar 

  158. Rocha NP, Ribeiro FM, Furr-Stimming E, Teixeira AL. Neuroimmunology of Huntington’s disease: revisiting evidence from human studies. Mediators Inflamm. 2016;2016:8653132.

    PubMed  PubMed Central  Google Scholar 

  159. Wakida NM, Lau AL, Nguyen J, Cruz GMS, Fote GM, Steffan JS, et al. Diminished LC3-Associated Phagocytosis by Huntington’s Disease Striatal Astrocytes. J Huntingt Dis. 2022;11:25–33.

    CAS  Google Scholar 

  160. Pereira CA de S, Medaglia N de C, Ureshino RP, Bincoletto C, et al. NAADP-Evoked Ca Signaling Leads to Mutant Huntingtin Aggregation and Autophagy Impairment in Murine Astrocytes. Int J Mol Sci [Internet]. 2023;24. Available from: https://doi.org/10.3390/ijms24065593.

  161. Crotti A, Benner C, Kerman BE, Gosselin D, Lagier-Tourenne C, Zuccato C, et al. Mutant Huntingtin promotes autonomous microglia activation via myeloid lineage-determining factors. Nat Neurosci. 2014;17:513–21.

    CAS  PubMed  PubMed Central  Google Scholar 

  162. Geloso MC, Corvino V, Marchese E, Serrano A, Michetti F, D’Ambrosi N. The dual role of microglia in ALS: mechanisms and therapeutic approaches. Front Aging Neurosci. 2017;9:242.

    PubMed  PubMed Central  Google Scholar 

  163. Massenzio F, Peña-Altamira E, Petralla S, Virgili M, Zuccheri G, Miti A, et al. Microglial overexpression of fALS-linked mutant SOD1 induces SOD1 processing impairment, activation and neurotoxicity and is counteracted by the autophagy inducer trehalose. Biochim Biophys Acta Mol Basis Dis. 2018;1864:3771–85.

    CAS  PubMed  Google Scholar 

  164. Granatiero V, Sayles NM, Savino AM, Konrad C, Kharas MG, Kawamata H, et al. Modulation of the IGF1R-MTOR pathway attenuates motor neuron toxicity of human ALS SOD1 astrocytes. Autophagy. 2021;17:4029–42.

    CAS  PubMed  PubMed Central  Google Scholar 

  165. BaofengFeng, Amponsah AE, Guo R, Liu X, Zhang J, Du X, et al. Autophagy-Mediated Inflammatory Cytokine Secretion in Sporadic ALS Patient iPSC-Derived Astrocytes. Oxid Med Cell Longev. 2022;2022:6483582.

    CAS  PubMed  PubMed Central  Google Scholar 

  166. Noh MY, Kwon MS, Oh KW, Nahm M, Park J, Kim YE, et al. Role of NCKAP1 in the Defective Phagocytic function of microglia-like cells derived from rapidly progressing sporadic ALS. Mol Neurobiol. 2023;60:4761–77.

    CAS  PubMed  PubMed Central  Google Scholar 

  167. Banerjee P, Mehta AR, Nirujogi RS, Cooper J, James OG, Nanda J, et al. Cell-autonomous immune dysfunction driven by disrupted autophagy in -ALS iPSC-derived microglia contributes to neurodegeneration. Sci Adv. 2023;9:eabq0651.

    CAS  PubMed  PubMed Central  Google Scholar 

  168. Lall D, Lorenzini I, Mota TA, Bell S, Mahan TE, Ulrich JD, et al. C9orf72 deficiency promotes microglial-mediated synaptic loss in aging and amyloid accumulation. Neuron. 2021;109:2275–91.e8.

    CAS  PubMed  PubMed Central  Google Scholar 

  169. Sako W, Ito H, Yoshida M, Koizumi H, Kamada M, Fujita K, et al. Nuclear factor κ B expression in patients with sporadic amyotrophic lateral sclerosis and hereditary amyotrophic lateral sclerosis with optineurin mutations. Clin Neuropathol. 2012;31:418–23.

    PubMed  Google Scholar 

  170. Prtenjaca N, Rob M, Alam MS, Markovinovic A, Stuani C, Buratti E, et al. Optineurin Deficiency and Insufficiency Lead to Higher Microglial TDP-43 Protein Levels. Int J Mol Sci [Internet]. 2022;23. Available from: https://doi.org/10.3390/ijms23126829.

  171. Berdyński M, Miszta P, Safranow K, Andersen PM, Morita M, Filipek S, et al. SOD1 mutations associated with amyotrophic lateral sclerosis analysis of variant severity. Sci Rep. 2022;12:103.

    PubMed  PubMed Central  Google Scholar 

  172. Bunton-Stasyshyn RKA, Saccon RA, Fratta P, Fisher EMC. SOD1 function and its implications for amyotrophic lateral sclerosis pathology: new and renascent themes. Neuroscientist. 2015;21:519–29.

    CAS  PubMed  Google Scholar 

  173. Marzella L, Ahlberg J, Glaumann H. Autophagy, heterophagy, microautophagy and crinophagy as the means for intracellular degradation. Virchows Arch B Cell Pathol Incl Mol Pathol. 1981;36:219–34.

    CAS  PubMed  Google Scholar 

  174. Kaushik S, Cuervo AM. Chaperone-mediated autophagy: a unique way to enter the lysosome world. Trends Cell Biol. 2012;22:407–17.

    CAS  PubMed  PubMed Central  Google Scholar 

  175. Settembre C, Fraldi A, Medina DL, Ballabio A. Signals from the lysosome: a control centre for cellular clearance and energy metabolism. Nat Rev Mol Cell Biol. 2013;14:283–96.

    CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Department of Neuroendocrinology, Centre of Postgraduate Medical Education, Warsaw, Mazovia, Poland

    Anna Litwiniuk

  2. Department of Animal Behavior and Welfare, Institute of Genetics and Animal Biotechnology, Polish Academy of Sciences, Jastrzębiec, Mazovia, Poland

    Grzegorz Roman Juszczak

  3. Department of Molecular Biology, Institute of Genetics and Animal Biotechnology, Polish Academy of Sciences, Jastrzębiec, Mazovia, Poland

    Adrian Mateusz Stankiewicz

  4. Department of Morphological Sciences, Faculty of Veterinary Medicine, Warsaw University of Life Sciences, Warsaw, Mazovia, Poland

    Kaja Urbańska

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AL, AMS and KU have written the first draft of the manuscript. AL, GRJ, AMS and KU revised and improved the first draft. All authors have seen and agreed on the finally submitted version of the manuscript. Figures were created with BioRender.com, with agreement numbers in order: JV24V4W7U0, DJ24V547S8, RX24V4XBLY, GY24V4XKDT, EO24V4XXGY, LS25T4EGT9.

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Litwiniuk, A., Juszczak, G.R., Stankiewicz, A.M. et al. The role of glial autophagy in Alzheimer’s disease. Mol Psychiatry 28, 4528–4539 (2023). https://doi.org/10.1038/s41380-023-02242-5

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