Skip to main content

Advertisement

SpringerLink
Log in

TREM2 and Microglia Contribute to the Synaptic Plasticity: from Physiology to Pathology

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Synapses are bridges for information transmission in the central nervous system (CNS), and synaptic plasticity is fundamental for the normal function of synapses, contributing substantially to learning and memory. Numerous studies have proven that microglia can participate in the occurrence and progression of neurodegenerative diseases (NDDs), such as Alzheimer’s disease (AD), by regulating synaptic plasticity. In this review, we summarize the main characteristics of synapses and synaptic plasticity under physiological and pathological conditions. We elaborate the origin and development of microglia and the two well-known microglial signaling pathways that regulate synaptic plasticity. We also highlight the unique role of triggering receptor expressed on myeloid cells 2 (TREM2) in microglia-mediated regulation of synaptic plasticity and its relationship with AD. Finally, we propose four possible ways in which TREM2 is involved in regulating synaptic plasticity. This review will help researchers understand how NDDs develop from the perspective of synaptic plasticity.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Data availability

Not applicable

References

  1. Biederer T, Kaeser PS, Blanpied TA (2017) Transcellular nanoalignment of synaptic function. Neuron 96:680–696

    Article  CAS  Google Scholar 

  2. Batool S, Raza H, Zaidi J, Riaz S, Hasan S, Syed NI (2019) Synapse formation: from cellular and molecular mechanisms to neurodevelopmental and neurodegenerative disorders. J Neurophysiol 121:1381–1397

    Article  CAS  Google Scholar 

  3. Mattson MP, Liu D (2002) Energetics and oxidative stress in synaptic plasticity and neurodegenerative disorders. Neuromolecular Med 2:215–231

    Article  CAS  Google Scholar 

  4. Barron JC, Hurley EP, Parsons MP (2021) Huntingtin and the synapse. Front Cell Neurosci 15:689332

    Article  CAS  Google Scholar 

  5. Nguyen M, Wong YC, Ysselstein D, Severino A, Krainc D (2019) Synaptic, mitochondrial, and lysosomal dysfunction in Parkinson’s disease. Trends Neurosci 42:140–149

    Article  CAS  Google Scholar 

  6. Rajendran L, Paolicelli RC (2018) Microglia-mediated synapse loss in Alzheimer’s disease. J Neurosci 38:2911–2919

    Article  CAS  Google Scholar 

  7. Citri A, Malenka RC (2008) Synaptic plasticity: multiple forms, functions, and mechanisms. Neuropsychopharmacology 33:18–41

    Article  Google Scholar 

  8. Andoh M, Koyama R (2021) Microglia regulate synaptic development and plasticity. Dev Neurobiol 81:568–590

    Article  Google Scholar 

  9. Hong S, Beja-Glasser VF, Nfonoyim BM, Frouin A, Li S, Ramakrishnan S, Merry KM, Shi Q et al (2016) Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science 352:712–716

    Article  CAS  Google Scholar 

  10. Lehrman EK, Wilton DK, Litvina EY, Welsh CA, Chang ST, Frouin A, Walker AJ, Heller MD et al (2018) CD47 protects synapses from excess microglia-mediated pruning during development. Neuron 100(120–134):e126

    Google Scholar 

  11. Pluvinage JV, Haney MS, Smith BAH, Sun J, Iram T, Bonanno L, Li L, Lee DP et al (2019) CD22 blockade restores homeostatic microglial phagocytosis in ageing brains. Nature 568:187–192

    Article  CAS  Google Scholar 

  12. Schafer DP, Lehrman EK, Kautzman AG, Koyama R, Mardinly AR, Yamasaki R, Ransohoff RM, Greenberg ME et al (2012) Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron 74:691–705

    Article  CAS  Google Scholar 

  13. Qin Q, Teng Z, Liu C, Li Q, Yin Y, Tang Y (2021) TREM2, microglia, and Alzheimer’s disease. Mech Ageing Dev 195:111438

    Article  CAS  Google Scholar 

  14. Keren-Shaul H, Spinrad A, Weiner A, Matcovitch-Natan O, Dvir-Szternfeld R, Ulland TK, David E, Baruch K et al (2017) A unique microglia type associated with restricting development of Alzheimer’s disease. Cell 169(1276–1290):e1217

    Google Scholar 

  15. Filipello F, Morini R, Corradini I, Zerbi V, Canzi A, Michalski B, Erreni M, Markicevic M et al (2018) The microglial innate immune receptor TREM2 is required for synapse elimination and normal brain connectivity. Immunity 48(979–991):e978

    Google Scholar 

  16. Cowan WM, Jessell TM, Zipursky SL (1997) Molecular and cellular approaches to neural development. Oxford University Press, New York

    Google Scholar 

  17. Grove EA, Fukuchi-Shimogori T (2003) Generating the cerebral cortical area map. Annu Rev Neurosci 26:355–380

    Article  CAS  Google Scholar 

  18. Skibo GG, Koval LM (1984) Ultrastructural characteristics of synaptogenesis in monolayer cultures of spinal cord. Neirofiziologiia 16:336–343

    CAS  Google Scholar 

  19. Jones TA, Bury SD, Adkins-Muir DL, Luke LM, Allred RP, Sakata JT (2003) Importance of behavioral manipulations and measures in rat models of brain damage and brain repair. ILAR J 44:144–152

    Article  CAS  Google Scholar 

  20. Lewis S (2011) Development: microglia go pruning. Nat Rev Neurosci 12:492–493

    Article  CAS  Google Scholar 

  21. Cardozo PL, de Lima IBQ, Maciel EMA, Silva NC, Dobransky T, Ribeiro FM (2019) Synaptic elimination in neurological disorders. Curr Neuropharmacol 17:1071–1095

    Article  CAS  Google Scholar 

  22. Neniskyte U, Gross CT (2017) Errant gardeners: glial-cell-dependent synaptic pruning and neurodevelopmental disorders. Nat Rev Neurosci 18:658–670

    Article  CAS  Google Scholar 

  23. Ho VM, Lee JA, Martin KC (2011) The cell biology of synaptic plasticity. Science 334:623–628

    Article  CAS  Google Scholar 

  24. Magee JC, Grienberger C (2020) Synaptic plasticity forms and functions. Annu Rev Neurosci 43:95–117

    Article  CAS  Google Scholar 

  25. Mansvelder HD, Verhoog MB, Goriounova NA (2019) Synaptic plasticity in human cortical circuits: cellular mechanisms of learning and memory in the human brain? Curr Opin Neurobiol 54:186–193

    Article  CAS  Google Scholar 

  26. Sudhof TC (2018) Towards an understanding of synapse formation. Neuron 100:276–293

    Article  CAS  Google Scholar 

  27. Sur M, Leamey CA (2001) Development and plasticity of cortical areas and networks. Nat Rev Neurosci 2:251–262

    Article  CAS  Google Scholar 

  28. Marrone DF, Petit TL (2002) The role of synaptic morphology in neural plasticity: structural interactions underlying synaptic power. Brain Res Brain Res Rev 38:291–308

    Article  Google Scholar 

  29. Bliss TV, Cooke SF (2011) Long-term potentiation and long-term depression: a clinical perspective. Clinics (Sao Paulo) 66(Suppl 1):3–17

    Article  Google Scholar 

  30. Malenka RC (1994) Synaptic plasticity in the hippocampus: LTP and LTD. Cell 78:535–538

    Article  CAS  Google Scholar 

  31. Carroll RC, Beattie EC, von Zastrow M, Malenka RC (2001) Role of AMPA receptor endocytosis in synaptic plasticity. Nat Rev Neurosci 2:315–324

    Article  CAS  Google Scholar 

  32. Derkach VA, Oh MC, Guire ES, Soderling TR (2007) Regulatory mechanisms of AMPA receptors in synaptic plasticity. Nat Rev Neurosci 8:101–113

    Article  CAS  Google Scholar 

  33. Lynch M, Sayin U, Golarai G, Sutula T (2000) NMDA receptor-dependent plasticity of granule cell spiking in the dentate gyrus of normal and epileptic rats. J Neurophysiol 84:2868–2879

    Article  CAS  Google Scholar 

  34. Skowronska K, Obara-Michlewska M, Czarnecka A, Dabrowska K, Zielinska M, Albrecht J (2019) Persistent overexposure to n-methyl-d-aspartate (nmda) calcium-dependently downregulates glutamine synthetase, aquaporin 4, and Kir4.1 channel in mouse cortical astrocytes. Neurotox Res 35:271–280

    Article  Google Scholar 

  35. Siegelbaum SA, Kandel ER (1991) Learning-related synaptic plasticity: LTP and LTD. Curr Opin Neurobiol 1:113–120

    Article  CAS  Google Scholar 

  36. Kullmann DM, Asztely F, Walker MC (2000) The role of mammalian ionotropic receptors in synaptic plasticity: LTP. LTD and epilepsy, Cell Mol Life Sci 57:1551–1561

    Article  CAS  Google Scholar 

  37. Riedel G, Platt B, Micheau J (2003) Glutamate receptor function in learning and memory. Behav Brain Res 140:1–47

    Article  CAS  Google Scholar 

  38. Bailey CH, Kandel ER, Harris KM (2015) Structural components of synaptic plasticity and memory consolidation. Cold Spring Harb Perspect Biol 7:a021758

    Article  Google Scholar 

  39. Nestler EJ (2013) Cellular basis of memory for addiction. Dialogues Clin Neurosci 15:431–443

    Article  Google Scholar 

  40. Dugger BN, Dickson DW (2017) Pathology of neurodegenerative diseases. Cold Spring Harb Perspect Biol 9:a028035

  41. McFerrin MB, Chi X, Cutter G, Yacoubian TA (2017) Dysregulation of 14-3-3 proteins in neurodegenerative diseases with Lewy body or Alzheimer pathology. Ann Clin Transl Neurol 4:466–477

    Article  CAS  Google Scholar 

  42. Shankar GM, Li S, Mehta TH, Garcia-Munoz A, Shepardson NE, Smith I, Brett FM, Farrell MA et al (2008) Amyloid-beta protein dimers isolated directly from Alzheimer’s brains impair synaptic plasticity and memory. Nat Med 14:837–842

    Article  CAS  Google Scholar 

  43. Lee L, Dale E, Staniszewski A, Zhang H, Saeed F, Sakurai M, Fa M, Orozco I et al (2014) Regulation of synaptic plasticity and cognition by SUMO in normal physiology and Alzheimer’s disease. Sci Rep 4:7190

    Article  CAS  Google Scholar 

  44. Chang EH, Savage MJ, Flood DG, Thomas JM, Levy RB, Mahadomrongkul V, Shirao T, Aoki C et al (2006) AMPA receptor downscaling at the onset of Alzheimer’s disease pathology in double knockin mice. PNAS 103:3410–3415

    Article  CAS  Google Scholar 

  45. Qu W, Yuan B, Liu J, Liu Q, Zhang X, Cui R, Yang W, Li B (2021) Emerging role of AMPA receptor subunit GluA1 in synaptic plasticity: implications for Alzheimer’s disease. Cell Prolif 54:e12959

    Article  CAS  Google Scholar 

  46. Spires-Jones TL, Hyman BT (2014) The intersection of amyloid beta and tau at synapses in Alzheimer’s disease. Neuron 82:756–771

    Article  CAS  Google Scholar 

  47. Voelzmann A, Okenve-Ramos P, Qu Y, Chojnowska-Monga M, Del Cano-Espinel M, Prokop A, Sanchez-Soriano N (2016) Tau and spectraplakins promote synapse formation and maintenance through Jun kinase and neuronal trafficking. eLife 5:e14694

  48. Si Z, Wang X, Zhang Z, Wang J, Li J, Li J, Li L, Li Y et al (2018) Heme oxygenase 1 induces tau oligomer formation and synapse aberrations in hippocampal neurons. J Alzheimers Dis 65:409–419

    Article  CAS  Google Scholar 

  49. Jadhav S, Katina S, Kovac A, Kazmerova Z, Novak M, Zilka N (2015) Truncated tau deregulates synaptic markers in rat model for human tauopathy. Front Cell Neurosci 9:24

    Article  Google Scholar 

  50. Shentu YP, Huo Y, Feng XL, Gilbert J, Zhang Q, Liuyang ZY, Wang XL, Wang G et al (2018) CIP2A causes tau/APP phosphorylation, synaptopathy, and memory deficits in Alzheimer’s disease. Cell Rep 24:713–723

    Article  CAS  Google Scholar 

  51. Deng H, Wang P, Jankovic J (2018) The genetics of Parkinson disease. Ageing Res Rev 42:72–85

    Article  CAS  Google Scholar 

  52. Stefanis L (2012) alpha-synuclein in Parkinson’s disease. Cold Spring Harb Perspect Med 2:a009399

    Article  Google Scholar 

  53. Taschenberger G, Garrido M, Tereshchenko Y, Bahr M, Zweckstetter M, Kugler S (2012) Aggregation of alphasynuclein promotes progressive in vivo neurotoxicity in adult rat dopaminergic neurons. Acta Neuropathol 123:671–683

    Article  CAS  Google Scholar 

  54. Pringsheim T, Wiltshire K, Day L, Dykeman J, Steeves T, Jette N (2012) The incidence and prevalence of Huntington’s disease: a systematic review and meta-analysis. Mov Disord 27:1083–1091

    Article  Google Scholar 

  55. Kremer B, Goldberg P, Andrew SE, Theilmann J, Telenius H, Zeisler J, Squitieri F, Lin B et al (1994) A worldwide study of the Huntington’s disease mutation. The sensitivity and specificity of measuring CAG repeats. N Engl J Med 330:1401–1406

    CAS  Google Scholar 

  56. Sepers MD, Raymond LA (2014) Mechanisms of synaptic dysfunction and excitotoxicity in Huntington’s disease. Drug Discov Today 19:990–996

    Article  CAS  Google Scholar 

  57. Perry VH, Hume DA, Gordon S (1985) Immunohistochemical localization of macrophages and microglia in the adult and developing mouse brain. Neuroscience 15:313–326

    Article  CAS  Google Scholar 

  58. Gomez Perdiguero E, Klapproth K, Schulz C, Busch K, Azzoni E, Crozet L, Garner H, Trouillet C et al (2015) Tissue-resident macrophages originate from yolk-sac-derived erythro-myeloid progenitors. Nature 518:547–551

    Article  Google Scholar 

  59. Ginhoux F, Greter M, Leboeuf M, Nandi S, See P, Gokhan S, Mehler MF, Conway SJ et al (2010) Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330:841–845

    Article  CAS  Google Scholar 

  60. Colonna M, Butovsky O (2017) Microglia function in the central nervous system during health and neurodegeneration. Annu Rev Immunol 35:441–468

    Article  CAS  Google Scholar 

  61. Jiang S, Bhaskar K (2017) Dynamics of the complement, cytokine, and chemokine systems in the regulation of synaptic function and dysfunction relevant to Alzheimer’s disease. J Alzheimers Dis 57:1123–1135

    Article  CAS  Google Scholar 

  62. Savage JC, Carrier M, Tremblay ME (2019) Morphology of microglia across contexts of health and disease. Methods Mol Biol 2034:13–26

    Article  CAS  Google Scholar 

  63. Loane DJ, Byrnes KR (2010) Role of microglia in neurotrauma. Neurotherapeutics 7:366–377

    Article  CAS  Google Scholar 

  64. Appel SH, Zhao W, Beers DR, Henkel JS (2011) The microglial-motoneuron dialogue in ALS. Acta Myol 30:4–8

    CAS  Google Scholar 

  65. Sica A, Mantovani A (2012) Macrophage plasticity and polarization: in vivo veritas. J Clin Invest 122:787–795

    Article  CAS  Google Scholar 

  66. Orihuela R, McPherson CA, Harry GJ (2016) Microglial M1/M2 polarization and metabolic states. Br J Pharmacol 173:649–665

    Article  CAS  Google Scholar 

  67. Deczkowska A, Keren-Shaul H, Weiner A, Colonna M, Schwartz M, Amit I (2018) Disease-associated microglia: a universal immune sensor of neurodegeneration. Cell 173:1073–1081

    Article  CAS  Google Scholar 

  68. Gerrits E, Brouwer N, Kooistra SM, Woodbury ME, Vermeiren Y, Lambourne M, Mulder J, Kummer M et al (2021) Distinct amyloid-beta and tau-associated microglia profiles in Alzheimer’s disease. Acta Neuropathol 141:681–696

    Article  CAS  Google Scholar 

  69. Faust TE, Gunner G, Schafer DP (2021) Mechanisms governing activity-dependent synaptic pruning in the developing mammalian CNS. Nat Rev Neurosci 22:657–673

    Article  CAS  Google Scholar 

  70. Tremblay ME, Lowery RL, Majewska AK (2010) Microglial interactions with synapses are modulated by visual experience. PLoS Biol 8:e1000527

    Article  Google Scholar 

  71. Paolicelli RC, Bolasco G, Pagani F, Maggi L, Scianni M, Panzanelli P, Giustetto M, Ferreira TA et al (2011) Synaptic pruning by microglia is necessary for normal brain development. Science 333:1456–1458

    Article  CAS  Google Scholar 

  72. Wang C, Yue H, Hu Z, Shen Y, Ma J, Li J, Wang XD, Wang L, Sun B et al (2020) Microglia mediate forgetting via complement-dependent synaptic elimination. Science 367:688–694

    Article  CAS  Google Scholar 

  73. Stevens B, Allen NJ, Vazquez LE, Howell GR, Christopherson KS, Nouri N, Micheva KD, Mehalow AK et al (2007) The classical complement cascade mediates CNS synapse elimination. Cell 131:1164–1178

    Article  CAS  Google Scholar 

  74. Scott-Hewitt N, Perrucci F, Morini R, Erreni M, Mahoney M, Witkowska A, Carey A, Faggiani E et al (2020) Local externalization of phosphatidylserine mediates developmental synaptic pruning by microglia. EMBO J 39:e105380

    Article  CAS  Google Scholar 

  75. Williams PA, Tribble JR, Pepper KW, Cross SD, Morgan BP, Morgan JE, John SW, Howell GR (2016) Inhibition of the classical pathway of the complement cascade prevents early dendritic and synaptic degeneration in glaucoma. Mol Neurodegener 11:26

    Article  Google Scholar 

  76. Hoshiko M, Arnoux I, Avignone E, Yamamoto N, Audinat E (2012) Deficiency of the microglial receptor CX3CR1 impairs postnatal functional development of thalamocortical synapses in the barrel cortex. J Neurosci 32:15106–15111

    Article  CAS  Google Scholar 

  77. Sokolowski JD, Chabanon-Hicks CN, Han CZ, Heffron DS, Mandell JW (2014) Fractalkine is a “find-me” signal released by neurons undergoing ethanol-induced apoptosis. Front Cell Neurosci 8:360

    Article  Google Scholar 

  78. Winter AN, Subbarayan MS, Grimmig B, Weesner JA, Moss L, Peters M, Weeber E, Nash K et al (2020) Two forms of CX3CL1 display differential activity and rescue cognitive deficits in CX3CL1 knockout mice. J Neuroinflammation 17:157

    Article  CAS  Google Scholar 

  79. Cordella F, Sanchini C, Rosito M, Ferrucci L, Pediconi N, Cortese B, Guerrieri F, Pascucci GR et al (2021) Antibiotics treatment modulates microglia-synapses interaction. Cells 10:2648

  80. Dworzak J, Renvoise B, Habchi J, Yates EV, Combadiere C, Knowles TP, Dobson CM, Blackstone C et al (2015) Neuronal Cx3cr1 deficiency protects against amyloid beta-induced neurotoxicity. PLoS ONE 10:e0127730

    Article  Google Scholar 

  81. Lauro C, Catalano M, Trettel F, Limatola C (2015) Fractalkine in the nervous system: neuroprotective or neurotoxic molecule? Ann N Y Acad Sci 1351:141–148

    Article  CAS  Google Scholar 

  82. Pawelec P, Ziemka-Nalecz M, Sypecka J, Zalewska T (2020) The impact of the CX3CL1/CX3CR1 axis in neurological disorders. Cells 9:2277

  83. Bertollini C, Ragozzino D, Gross C, Limatola C, Eusebi F (2006) Fractalkine/CX3CL1 depresses central synaptic transmission in mouse hippocampal slices. Neuropharmacology 51:816–821

    Article  CAS  Google Scholar 

  84. Zhang J, Malik A, Choi HB, Ko RW, Dissing-Olesen L, MacVicar BA (2014) Microglial CR3 activation triggers long-term synaptic depression in the hippocampus via NADPH oxidase. Neuron 82:195–207

    Article  CAS  Google Scholar 

  85. Owens R, Grabert K, Davies CL, Alfieri A, Antel JP, Healy LM, McColl BW (2017) Divergent neuroinflammatory regulation of microglial TREM expression and involvement of NF-kappaB. Front Cell Neurosci 11:56

    Google Scholar 

  86. Jay TR, von Saucken VE, Munoz B, Codocedo JF, Atwood BK, Lamb BT, Landreth GE (2019) TREM2 is required for microglial instruction of astrocytic synaptic engulfment in neurodevelopment. Glia 67:1873–1892

    Google Scholar 

  87. Parhizkar S, Arzberger T, Brendel M, Kleinberger G, Deussing M, Focke C, Nuscher B, Xiong M et al (2019) Loss of TREM2 function increases amyloid seeding but reduces plaque-associated ApoE. Nat Neurosci 22:191–204

    Article  CAS  Google Scholar 

  88. Kober DL, Brett TJ (2017) TREM2-ligand interactions in health and disease. J Mol Biol 429:1607–1629

    Article  CAS  Google Scholar 

  89. Zhao Y, Wu X, Li X, Jiang LL, Gui X, Liu Y, Sun Y, Zhu B et al (2018) TREM2 is a receptor for beta-amyloid that mediates microglial function. Neuron 97(1023–1031):e1027

    Google Scholar 

  90. Deczkowska A, Weiner A, Amit I (2020) The physiology, pathology, and potential therapeutic applications of the TREM2 signaling pathway. Cell 181:1207–1217

    Article  CAS  Google Scholar 

  91. Peng Q, Malhotra S, Torchia JA, Kerr WG, Coggeshall KM, Humphrey MB (2010) TREM2- and DAP12-dependent activation of PI3K requires DAP10 and is inhibited by SHIP1. Sci Signal 3:ra38

  92. Kaifu T, Nakahara J, Inui M, Mishima K, Momiyama T, Kaji M, Sugahara A, Koito H et al (2003) Osteopetrosis and thalamic hypomyelinosis with synaptic degeneration in DAP12-deficient mice. J Clin Invest 111:323–332

    Article  CAS  Google Scholar 

  93. Qu W, Li L (2020) Loss of TREM2 confers resilience to synaptic and cognitive impairment in aged mice. J Neurosci 40:9552–9563

    Article  CAS  Google Scholar 

  94. Griciuc A, Patel S, Federico AN, Choi SH, Innes BJ, Oram MK, Cereghetti G, McGinty D et al (2019) TREM2 acts downstream of CD33 in modulating microglial pathology in alzheimer’s disease. Neuron 103(820–835):e827

    Google Scholar 

  95. Zhao L (2019) CD33 in Alzheimer’s disease - biology, pathogenesis, and therapeutics: a mini-review. Gerontology 65:323–331

    Article  CAS  Google Scholar 

  96. Abduljaleel Z, Al-Allaf FA, Khan W, Athar M, Shahzad N, Taher MM, Elrobh M, Alanazi MS et al (2014) Evidence of trem2 variant associated with triple risk of Alzheimer’s disease. PLoS ONE 9:e92648

    Article  Google Scholar 

  97. Jonsson T, Stefansson H, Steinberg S, Jonsdottir I, Jonsson PV, Snaedal J, Bjornsson S, Huttenlocher J et al (2013) Variant of TREM2 associated with the risk of Alzheimer’s disease. N Engl J Med 368:107–116

    Article  CAS  Google Scholar 

  98. Wunderlich P, Glebov K, Kemmerling N, Tien NT, Neumann H, Walter J (2013) Sequential proteolytic processing of the triggering receptor expressed on myeloid cells-2 (TREM2) protein by ectodomain shedding and gamma-secretase-dependent intramembranous cleavage. J Biol Chem 288:33027–33036

    Article  CAS  Google Scholar 

  99. Ulland TK, Colonna M (2018) TREM2 - a key player in microglial biology and Alzheimer disease. Nat Rev Neurol 14:667–675

    Article  CAS  Google Scholar 

  100. Kleinberger G, Yamanishi Y, Suarez-Calvet M, Czirr E, Lohmann E, Cuyvers E, Struyfs H, Pettkus N et al (2014) TREM2 mutations implicated in neurodegeneration impair cell surface transport and phagocytosis. Sci Transl Med 6:243ra86

  101. Sayed FA, Telpoukhovskaia M, Kodama L, Li Y, Zhou Y, Le D, Hauduc A, Ludwig C et al (2018) Differential effects of partial and complete loss of TREM2 on microglial injury response and tauopathy. PNAS 115:10172–10177

    Article  CAS  Google Scholar 

  102. Lee SH, Meilandt WJ, Xie L, Gandham VD, Ngu H, Barck KH, Rezzonico MG, Imperio J et al (2021) Trem2 restrains the enhancement of tau accumulation and neurodegeneration by beta-amyloid pathology. Neuron 109(1283–1301):e1286

    Google Scholar 

  103. Ruganzu JB, Zheng Q, Wu X, He Y, Peng X, Jin H, Zhou J, Ma R et al (2021) TREM2 overexpression rescues cognitive deficits in APP/PS1 transgenic mice by reducing neuroinflammation via the JAK/STAT/SOCS signaling pathway. Exp Neurol 336:113506

    Article  CAS  Google Scholar 

  104. Reifschneider A, Robinson S, van Lengerich B, Gnorich J, Logan T, Heindl S, Vogt MA, Weidinger E et al (2022) Loss of TREM2 rescues hyperactivation of microglia, but not lysosomal deficits and neurotoxicity in models of progranulin deficiency. EMBO J 41:e109108

    Article  CAS  Google Scholar 

  105. Krasemann S, Madore C, Cialic R, Baufeld C, Calcagno N, El Fatimy R, Beckers L, O’Loughlin E et al (2017) The TREM2-APOE pathway drives the transcriptional phenotype of dysfunctional microglia in neurodegenerative diseases. Immunity 47(566–581):e569

    Google Scholar 

  106. Chung WS, Clarke LE, Wang GX, Stafford BK, Sher A, Chakraborty C, Joung J, Foo LC et al (2013) Astrocytes mediate synapse elimination through MEGF10 and MERTK pathways. Nature 504:394–400

    Article  CAS  Google Scholar 

  107. Wang Y, Fu WY, Cheung K, Hung KW, Chen C, Geng H, Yung WH, Qu JY et al (2021) Astrocyte-secreted IL-33 mediates homeostatic synaptic plasticity in the adult hippocampus. PNAS 118:e2020810118

  108. Nguyen AT, Wang K, Hu G, Wang X, Miao Z, Azevedo JA, Suh E, Van Deerlin VM et al (2020) APOE and TREM2 regulate amyloid-responsive microglia in Alzheimer’s disease. Acta Neuropathol 140:477–493

    Article  CAS  Google Scholar 

  109. Xiang X, Werner G, Bohrmann B, Liesz A, Mazaheri F, Capell A, Feederle R, Knuesel I et al (2016) TREM2 deficiency reduces the efficacy of immunotherapeutic amyloid clearance. EMBO Mol Med 8:992–1004

    Article  CAS  Google Scholar 

  110. Price BR, Sudduth TL, Weekman EM, Johnson S, Hawthorne D, Woolums A, Wilcock DM (2020) Therapeutic Trem2 activation ameliorates amyloid-beta deposition and improves cognition in the 5XFAD model of amyloid deposition. J Neuroinflammation 17:238

    Article  Google Scholar 

  111. Wang S, Mustafa M, Yuede CM, Salazar SV, Kong P, Long H, Ward M, Siddiqui O et al (2020) Anti-human TREM2 induces microglia proliferation and reduces pathology in an Alzheimer's disease model. J Exp Med 217:e20200785

  112. Fassler M, Rappaport MS, Cuno CB, George J (2021) Engagement of TREM2 by a novel monoclonal antibody induces activation of microglia and improves cognitive function in Alzheimer’s disease models. J Neuroinflammation 18:19

    Article  CAS  Google Scholar 

  113. Schlepckow K, Monroe KM, Kleinberger G, Cantuti-Castelvetri L, Parhizkar S, Xia D, Willem M, Werner G et al (2020) Enhancing protective microglial activities with a dual function TREM2 antibody to the stalk region. EMBO Mol Med 12:e11227

    Article  CAS  Google Scholar 

  114. Zhao P, Xu Y, Jiang L, Fan X, Li L, Li X, Arase H, Zhao Y et al (2022) A tetravalent TREM2 agonistic antibody reduced amyloid pathology in a mouse model of Alzheimer's disease. Sci Transl Med 14:eabq0095

Download references

Funding

This work was supported by Beijing Hospitals Authority’s Ascent Plan (DFL20220703), Young Elite Scientists Sponsorship Program by CAST (2021QNRC001), Beijing Hospitals Authority Innovation Studio of Young Staff Funding (202118), Beijing Nova Program (Z211100002121051), Beijing Natural Science Foundation (JQ19024), and the National Natural Science Foundation of China (82220108009, 81970996, 82201568).

Author information

Author notes

  1. Chao-Ji Yu and Meng Wang contributed equally to this work.

Authors and Affiliations

  1. Innovation Center for Neurological Disorders, Department of Neurology, National Center for Neurological Disorders, Xuanwu Hospital, Capital Medical University, Beijing, China

    Chao-Ji Yu, Meng Wang, Rui-Yang Li, Tao Wei, Han-Chen Yang, Yun-Si Yin, Ying-Xin Mi, Qi Qin & Yi Tang

Authors
  1. Chao-Ji Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Meng Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rui-Yang Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tao Wei
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Han-Chen Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yun-Si Yin
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ying-Xin Mi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Qi Qin
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yi Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

QQ, YT, CJY, and WM drafted the concept. CJY and MW wrote major parts. RYL and TW provided critical feedback and revised the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Qi Qin or Yi Tang.

Ethics declarations

Ethics Approval and Consent to Participate

Not applicable.

Consent for Publication

Not applicable.

Competing Interests

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yu, CJ., Wang, M., Li, RY. et al. TREM2 and Microglia Contribute to the Synaptic Plasticity: from Physiology to Pathology. Mol Neurobiol 60, 512–523 (2023). https://doi.org/10.1007/s12035-022-03100-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-022-03100-1

Keywords

Search

Navigation