Skip to main content
SpringerLink
Log in

Microglial Dysfunction in Brain Aging and Neurodegeneration

  • Living reference work entry
  • First Online:
Handbook of Immunosenescence

Abstract

Aging impacts nearly every tissue and function in an organism and presents the primary risk factor for major human diseases, including neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease. The underlying cause of aging is likely a multifaceted yet interconnected tangle of processes, but there is a growing evidence that in the brain, microglia have a major role. Microglia are the resident immune cells in the brain. They are involved in development and maintenance of the brain through secretion of growth factors and clearance of unwanted cellular material, and it is thought that these functions deteriorate with age. Moreover, myelin fragments, abnormal protein assemblies, and cellular debris, which increase with aging and neurodegeneration, may overload the phagolysosomal capacity of microglia, leading to their abnormal activation and the secretion of detrimental inflammatory factors. To restore brain homeostasis during aging and disease, it may be necessary to increase beneficial microglial functions in addition to blocking detrimental ones.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution

Institutional subscriptions

References

  • Aguzzi A, Barres BA, Bennett ML (2013) Microglia: scapegoat, saboteur, or something else? Science 339:156–161

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • al-Ali SY, al-Hussain SM (1996) An ultrastructural study of the phagocytic activity of astrocytes in adult rat brain. J Anat 188(Pt 2):257–262

    PubMed  PubMed Central  Google Scholar 

  • Appelqvist H, Waster P, Kagedal K, Ollinger K (2013) The lysosome: from waste bag to potential therapeutic target. J Mol Cell Biol 5:214–226

    Article  CAS  PubMed  Google Scholar 

  • Bliederhaeuser C, Grozdanov V, Speidel A, Zondler L, Ruf WP, Bayer H, Kiechle M, Feiler MS, Freischmidt A, Brenner D et al (2016) Age-dependent defects of alpha-synuclein oligomer uptake in microglia and monocytes. Acta Neuropathol 131:379–391

    Article  CAS  PubMed  Google Scholar 

  • Brunk UT, Terman A (2002) The mitochondrial-lysosomal axis theory of aging: accumulation of damaged mitochondria as a result of imperfect autophagocytosis. Eur J Biochem 269:1996–2002

    Article  CAS  PubMed  Google Scholar 

  • Carmona-Gutierrez D, Hughes AL, Madeo F, Ruckenstuhl C (2016) The crucial impact of lysosomes in aging and longevity. Ageing Res Rev 32:2–12

    Article  CAS  PubMed  Google Scholar 

  • Cho MH, Cho K, Kang HJ, Jeon EY, Kim HS, Kwon HJ, Kim HM, Kim DH, Yoon SY (2014) Autophagy in microglia degrades extracellular beta-amyloid fibrils and regulates the NLRP3 inflammasome. Autophagy 10:1761–1775

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Colacurcio DJ, Nixon RA (2016) Disorders of lysosomal acidification-The emerging role of v-ATPase in aging and neurodegenerative disease. Ageing Res Rev 32:75–88

    Article  CAS  PubMed  Google Scholar 

  • Cookson MR (2015) LRRK2 pathways leading to neurodegeneration. Curr Neurol Neurosci Rep 15:42

    Article  PubMed  Google Scholar 

  • Cuervo AM, Macian F (2014) Autophagy and the immune function in aging. Curr Opin Immunol 29:97–104

    Article  CAS  PubMed  Google Scholar 

  • Davalos D, Grutzendler J, Yang G, Kim JV, Zuo Y, Jung S, Littman DR, Dustin ML, Gan WB (2005) ATP mediates rapid microglial response to local brain injury in vivo. Nat Neurosci 8:752–758

    Article  CAS  PubMed  Google Scholar 

  • Dawson TM, Dawson VL (2003) Molecular pathways of neurodegeneration in Parkinson’s disease. Science 302:819–822

    Article  CAS  PubMed  Google Scholar 

  • Derecki NC, Cronk JC, Lu Z, Xu E, Abbott SB, Guyenet PG, Kipnis J (2012) Wild-type microglia arrest pathology in a mouse model of Rett syndrome. Nature 484:105–109

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dominguez-Bautista JA, Klinkenberg M, Brehm N, Subramaniam M, Kern B, Roeper J, Auburger G, Jendrach M (2015) Loss of lysosome-associated membrane protein 3 (LAMP3) enhances cellular vulnerability against proteasomal inhibition. Eur J Cell Biol 94:148–161

    Article  CAS  PubMed  Google Scholar 

  • Eichhoff G, Busche MA, Garaschuk O (2008) In vivo calcium imaging of the aging and diseased brain. Eur J Nucl Med Mol Imaging 35(Suppl 1):S99–106

    Article  PubMed  Google Scholar 

  • Fraldi A, Klein AD, Medina DL, Settembre C (2016) Brain disorders due to lysosomal dysfunction. Annu Rev Neurosci 39:277–295

    Article  CAS  PubMed  Google Scholar 

  • Fu R, Shen Q, Xu P, Luo JJ, Tang Y (2014) Phagocytosis of microglia in the central nervous system diseases. Mol Neurobiol 49:1422–1434

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gan-Or Z, Dion PA, Rouleau GA (2015) Genetic perspective on the role of the autophagy-lysosome pathway in Parkinson disease. Autophagy 11:1443–1457

    Article  PubMed  PubMed Central  Google Scholar 

  • Gardai SJ, Mao W, Schule B, Babcock M, Schoebel S, Lorenzana C, Alexander J, Kim S, Glick H, Hilton K et al (2013) Elevated alpha-synuclein impairs innate immune cell function and provides a potential peripheral biomarker for Parkinson’s disease. PLoS One 8:e71634

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gray DA, Woulfe J (2005) Lipofuscin and aging: a matter of toxic waste. Sci Aging Knowl Environ 2005:re1

    Google Scholar 

  • Herzig MC, Kolly C, Persohn E, Theil D, Schweizer T, Hafner T, Stemmelen C, Troxler TJ, Schmid P, Danner S et al (2011) LRRK2 protein levels are determined by kinase function and are crucial for kidney and lung homeostasis in mice. Hum Mol Genet 20:4209–4223

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hinkle KM, Yue M, Behrouz B, Dachsel JC, Lincoln SJ, Bowles EE, Beevers JE, Dugger B, Winner B, Prots I et al (2012) LRRK2 knockout mice have an intact dopaminergic system but display alterations in exploratory and motor co-ordination behaviors. Mol Neurodegener 7:25

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hsieh CH, Shaltouki A, Gonzalez AE, Bettencourt da Cruz A, Burbulla LF, St Lawrence E, Schule B, Krainc D, Palmer TD, Wang X (2016) Functional impairment in miro degradation and mitophagy is a shared feature in familial and sporadic Parkinson’s disease. Cell Stem Cell 19:709–724

    Article  CAS  PubMed  Google Scholar 

  • Ivatt RM, Whitworth AJ (2014) SREBF1 links lipogenesis to mitophagy and sporadic Parkinson disease. Autophagy 10:1476–7

    Google Scholar 

  • Jiang P, Mizushima N (2014) Autophagy and human diseases. Cell Res 24:69–79

    Article  CAS  PubMed  Google Scholar 

  • Kim I, Rodriguez-Enriquez S, Lemasters JJ (2007) Selective degradation of mitochondria by mitophagy. Arch Biochem Biophys 462:245–253

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kim HJ, Cho MH, Shim WH, Kim JK, Jeon EY, Kim DH, Yoon SY (2016). Deficient autophagy in microglia impairs synaptic pruning and causes social behavioral defects. Mol Psychiatry. 2016 Jul 12. Epub ahead of print

    Google Scholar 

  • Kurzawa-Akanbi M, Hanson PS, Blain PG, Lett DJ, McKeith IG, Chinnery PF, Morris CM (2012) Glucocerebrosidase mutations alter the endoplasmic reticulum and lysosomes in Lewy body disease. J Neurochem 123:298–309

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lapierre LR, De Magalhaes Filho CD, McQuary PR, Chu CC, Visvikis O, Chang JT, Gelino S, Ong B, Davis AE, Irazoqui JE et al (2013) The TFEB orthologue HLH-30 regulates autophagy and modulates longevity in Caenorhabditis elegans. Nat Commun 4:2267

    PubMed  Google Scholar 

  • Lill CM, Roehr JT, McQueen MB, Kavvoura FK, Bagade S, Schjeide BM, Schjeide LM, Meissner E, Zauft U, Allen NC et al (2012) Comprehensive research synopsis and systematic meta-analyses in Parkinson’s disease genetics: the PDGene database. PLoS Genet 8:e1002548

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lin MT, Simon DK, Ahn CH, Kim LM, Beal MF (2002) High aggregate burden of somatic mtDNA point mutations in aging and Alzheimer’s disease brain. Hum Mol Genet 11:133–145

    Article  CAS  PubMed  Google Scholar 

  • Liu J, Zhou Y, Wang Y, Fong H, Murray TM, Zhang J (2007) Identification of proteins involved in microglial endocytosis of alpha-synuclein. J Proteome Res 6:3614–3627

    Article  CAS  PubMed  Google Scholar 

  • Lu Z, Elliott MR, Chen Y, Walsh JT, Klibanov AL, Ravichandran KS, Kipnis J (2011) Phagocytic activity of neuronal progenitors regulates adult neurogenesis. Nat Cell Biol 13:1076–1083

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lucin KM, O'Brien CE, Bieri G, Czirr E, Mosher KI, Abbey RJ, Mastroeni DF, Rogers J, Spencer B, Masliah E, Wyss-Coray T (2013) Microglial beclin 1 regulates retromer trafficking and phagocytosis and is impaired in Alzheimer’s disease. Neuron 79:873–886

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lucking CB, Durr A, Bonifati V, Vaughan J, De Michele G, Gasser T, Harhangi BS, Meco G, Denefle P, Wood NW et al (2000) Association between early-onset Parkinson's disease and mutations in the parkin gene. N Engl J Med 342:1560–1567

    Article  CAS  PubMed  Google Scholar 

  • Ma W, Coon S, Zhao L, Fariss RN, Wong WT (2013) A2E accumulation influences retinal microglial activation and complement regulation. Neurobiol Aging 34:943–960

    Article  CAS  PubMed  Google Scholar 

  • Madeo F, Tavernarakis N, Kroemer G (2010) Can autophagy promote longevity? Nat Cell Biol 12:842–846

    Article  CAS  PubMed  Google Scholar 

  • Manzanillo PS, Ayres JS, Watson RO, Collins AC, Souza G, Rae CS, Schneider DS, Nakamura K, Shiloh MU, Cox JS (2013) The ubiquitin ligase parkin mediates resistance to intracellular pathogens. Nature 501:512–516

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Menzies FM, Fleming A, Rubinsztein DC (2015) Compromised autophagy and neurodegenerative diseases. Nat Rev Neurosci 16:345–357

    Article  CAS  PubMed  Google Scholar 

  • Morsch M, Radford R, Lee A, Don EK, Badrock AP, Hall TE, Cole NJ, Chung R (2015) In vivo characterization of microglial engulfment of dying neurons in the zebrafish spinal cord. Front Cell Neurosci 9:321

    Article  PubMed  PubMed Central  Google Scholar 

  • Mosher KI, Wyss-Coray T (2014) Microglial dysfunction in brain aging and Alzheimer’s disease. Biochem Pharmacol 88:594–604

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nalls MA, Pankratz N, Lill CM, Do CB, Hernandez DG, Saad M, DeStefano AL, Kara E, Bras J, Sharma M et al (2014) Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson's disease. Nat Genet 46:989–993

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Narendra DP, Jin SM, Tanaka A, Suen DF, Gautier CA, Shen J, Cookson MR, Youle RJ (2010) PINK1 is selectively stabilized on impaired mitochondria to activate Parkin. PLoS Biol 8:e1000298

    Article  PubMed  PubMed Central  Google Scholar 

  • Nimmerjahn A, Kirchhoff F, Helmchen F (2005) Resting microglial cells are highly dynamic surveillance of brain parenchyma in vivo. Science 308:1314–1318

    Article  CAS  PubMed  Google Scholar 

  • Parkhurst CN, Yang G, Ninan I, Savas JN, Yates JR 3rd, Lafaille JJ, Hempstead BL, Littman DR, Gan WB (2013) Microglia promote learning-dependent synapse formation through brain-derived neurotrophic factor. Cell 155:1596–1609

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Perry VH, Holmes C (2014) Microglial priming in neurodegenerative disease. Nat Rev Neurol 10:217–224

    Article  CAS  PubMed  Google Scholar 

  • Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, Dutra A, Pike B, Root H, Rubenstein J, Boyer R et al (1997) Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science 276:2045–2047

    Article  CAS  PubMed  Google Scholar 

  • Ritzel RM, Patel AR, Pan S, Crapser J, Hammond M, Jellison E, McCullough LD (2015) Age- and location-related changes in microglial function. Neurobiol Aging 36:2153–2163

    Article  CAS  PubMed  Google Scholar 

  • Rubinsztein DC, Marino G, Kroemer G (2011) Autophagy and aging. Cell 146:682–695

    Article  CAS  PubMed  Google Scholar 

  • Russo I, Bubacco L, Greggio E (2014) LRRK2 and neuroinflammation: partners in crime in Parkinson’s disease? J Neuroinflammation 11:52

    Article  PubMed  PubMed Central  Google Scholar 

  • Safaiyan S, Kannaiyan N, Snaidero N, Brioschi S, Biber K, Yona S, Edinger AL, Jung S, Rossner MJ, Simons M (2016) Age-related myelin degradation burdens the clearance function of microglia during aging. Nat Neurosci 19:995–998

    Article  CAS  PubMed  Google Scholar 

  • Salter MW, Beggs S (2014) Sublime microglia: expanding roles for the guardians of the CNS. Cell 158:15–24

    Article  CAS  PubMed  Google Scholar 

  • Sardiello M, Palmieri M, di Ronza A, Medina DL, Valenza M, Gennarino VA, Di Malta C, Donaudy F, Embrione V, Polishchuk RS et al (2009) A gene network regulating lysosomal biogenesis and function. Science 325:473–477

    CAS  PubMed  Google Scholar 

  • Schafer DP, Stevens B (2013) Phagocytic glial cells: sculpting synaptic circuits in the developing nervous system. Curr Opin Neurobiol 23:1034–1040

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schapansky J, Nardozzi JD, LaVoie MJ (2015) The complex relationships between microglia, alpha-synuclein, and LRRK2 in Parkinson’s disease. Neuroscience 302:74–88

    Article  CAS  PubMed  Google Scholar 

  • Seehafer SS, Pearce DA (2006) You say lipofuscin, we say ceroid: defining autofluorescent storage material. Neurobiol Aging 27:576–588

    Article  CAS  PubMed  Google Scholar 

  • Settembre C, Medina DL (2015) TFEB and the CLEAR network. Methods Cell Biol 126:45–62

    Article  PubMed  Google Scholar 

  • Shen K, Sidik H, Talbot WS (2016) The rag-ragulator complex regulates lysosome function and phagocytic flux in microglia. Cell Rep 14:547–559

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sierra A, Gottfried-Blackmore AC, McEwen BS, Bulloch K (2007) Microglia derived from aging mice exhibit an altered inflammatory profile. Glia 55:412–424

    Article  PubMed  Google Scholar 

  • Sierra A, Encinas JM, Deudero JJ, Chancey JH, Enikolopov G, Overstreet-Wadiche LS, Tsirka SE, Maletic-Savatic M (2010) Microglia shape adult hippocampal neurogenesis through apoptosis-coupled phagocytosis. Cell Stem Cell 7:483–495

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Singh R, Kaushik S, Wang Y, Xiang Y, Novak I, Komatsu M, Tanaka K, Cuervo AM, Czaja MJ (2009) Autophagy regulates lipid metabolism. Nature 458:1131–1135

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stefanova N, Fellner L, Reindl M, Masliah E, Poewe W, Wenning GK (2011) Toll-like receptor 4 promotes alpha-synuclein clearance and survival of nigral dopaminergic neurons. Am J Pathol 179:954–963

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Szweda PA, Camouse M, Lundberg KC, Oberley TD, Szweda LI (2003) Aging, lipofuscin formation, and free radical-mediated inhibition of cellular proteolytic systems. Ageing Res Rev 2:383–405

    Article  CAS  PubMed  Google Scholar 

  • Tomihari M, Hwang SH, Chung JS, Cruz PD Jr, Ariizumi K (2009) Gpnmb is a melanosome-associated glycoprotein that contributes to melanocyte/keratinocyte adhesion in a RGD-dependent fashion. Exp Dermatol 18:586–595

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tran TA, Nguyen AD, Chang J, Goldberg MS, Lee JK, Tansey MG (2011) Lipopolysaccharide and tumor necrosis factor regulate Parkin expression via nuclear factor-kappa B. PLoS One 6:e23660

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vaughan DW, Peters A (1974) Neuroglial cells in the cerebral cortex of rats from young adulthood to old age: an electron microscope study. J Neurocytol 3:405–429

    Article  CAS  PubMed  Google Scholar 

  • Wong WT (2013) Microglial aging in the healthy CNS: phenotypes, drivers, and rejuvenation. Front Cell Neurosci 7:22

    CAS  PubMed  PubMed Central  Google Scholar 

  • Xu H, Chen M, Mayer EJ, Forrester JV, Dick AD (2007) Turnover of resident retinal microglia in the normal adult mouse. Glia 55:1189–1198

    Article  PubMed  Google Scholar 

  • Xu H, Chen M, Manivannan A, Lois N, Forrester JV (2008) Age-dependent accumulation of lipofuscin in perivascular and subretinal microglia in experimental mice. Aging Cell 7:58–68

    Article  CAS  PubMed  Google Scholar 

  • Yue Z, Zhong Y (2010) From a global view to focused examination: understanding cellular function of lipid kinase VPS34-Beclin 1 complex in autophagy. J Mol Cell Biol 2:305–307

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang W, Wang T, Pei Z, Miller DS, Wu X, Block ML, Wilson B, Zhang W, Zhou Y, Hong JS et al (2005) Aggregated alpha-synuclein activates microglia: a process leading to disease progression in Parkinson's disease. FASEB J 19:533–42

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA

    Julia Marschallinger & Tony Wyss-Coray

  2. Paul F. Glenn Center for the Biology of Aging, Stanford University School of Medicine, Stanford, CA, USA

    Julia Marschallinger & Tony Wyss-Coray

  3. California Institute for Quantitative Biosciences, University of California Berkeley, Berkeley, CA, USA

    Kira Irving Mosher

  4. Center for Tissue Regeneration, Repair and Restoration, Veterans Administration Palo Alto Health Care System, Palo Alto, CA, USA

    Tony Wyss-Coray

  5. Stanford School of Medicine, Wyss-Coray Laboratory, Stanford University, Palo Alto, CA, USA

    Tony Wyss-Coray

Authors
  1. Julia Marschallinger
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kira Irving Mosher
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tony Wyss-Coray
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Tony Wyss-Coray .

Editor information

Editors and Affiliations

  1. Division of Geriatrics Research Center on Aging, University of Sherbrooke Dept. of Medicine, Sherbrooke, Québec, Canada

    Tamas Fulop

  2. Dept of Experimental Pathology, University of Bologna, Bologna, Italy

    Claudio Franceschi

  3. Institute for Health and Life Sciences, Tokyo, Japan

    Katsuiku Hirokawa

  4. Center for Medical Research, University of Tübingen, Tübingen, Germany

    Graham Pawelec

Section Editor information

  1. Research Center on Aging, Department of Medicine, Immunology Graduate Programme, Faculty of Medicine, University of Sherbrooke, Sherbrooke, Quebec, Canada

    Tamas Fulop

Rights and permissions

Reprints and permissions

Copyright information

© 2018 Springer International Publishing AG

About this entry

Cite this entry

Marschallinger, J., Mosher, K.I., Wyss-Coray, T. (2018). Microglial Dysfunction in Brain Aging and Neurodegeneration. In: Fulop, T., Franceschi, C., Hirokawa, K., Pawelec, G. (eds) Handbook of Immunosenescence. Springer, Cham. https://doi.org/10.1007/978-3-319-64597-1_149-1

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-64597-1_149-1

  • Received:

  • Accepted:

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-64597-1

  • Online ISBN: 978-3-319-64597-1

  • eBook Packages: Springer Reference Biomedicine and Life SciencesReference Module Biomedical and Life Sciences

Publish with us

Policies and ethics

Search

Navigation