REFERENCES

1. Wendeln AC, Degenhardt K, Kaurani L, et al. Innate immune memory in the brain shapes neurological disease hallmarks. Nature 2018;556:332-8.

2. Engelhardt B, Vajkoczy P, Weller RO. The movers and shapers in immune privilege of the CNS. Nat Immunol 2017;18:123-31.

3. van Langelaar J, Rijvers L, Smolders J, van Luijn MM. B and T cells driving multiple sclerosis: identity, mechanisms and potential triggers. Front Immunol 2020;11:760.

4. Jeltsch-David H, Muller S. Neuropsychiatric systemic lupus erythematosus: pathogenesis and biomarkers. Nat Rev Neurol 2014;10:579-96.

5. Gelb S, Stock AD, Anzi S, Putterman C, Ben-Zvi A. Mechanisms of neuropsychiatric lupus: The relative roles of the blood-cerebrospinal fluid barrier versus blood-brain barrier. J Autoimmun 2018;91:34-44.

6. Arvanitis CD, Ferraro GB, Jain RK. The blood-brain barrier and blood-tumour barrier in brain tumours and metastases. Nat Rev Cancer 2020;20:26-41.

7. Boire A, Brastianos PK, Garzia L, Valiente M. Brain metastasis. Nat Rev Cancer 2020;20:4-11.

8. Forrester JV, McMenamin PG, Dando SJ. CNS infection and immune privilege. Nat Rev Neurosci 2018;19:655-71.

9. Viggars AP, Wharton SB, Simpson JE, et al. Alterations in the blood brain barrier in ageing cerebral cortex in relationship to Alzheimer-type pathology: a study in the MRC-CFAS population neuropathology cohort. Neurosci Lett 2011;505:25-30.

10. Montagne A, Zhao Z, Zlokovic BV. Alzheimer’s disease: A matter of blood-brain barrier dysfunction? J Exp Med 2017;214:3151-69.

11. Zlokovic BV. Neurovascular pathways to neurodegeneration in Alzheimer’s disease and other disorders. Nat Rev Neurosci 2011;12:723-38.

12. Yang AC, Stevens MY, Chen MB, et al. Physiological blood-brain transport is impaired with age by a shift in transcytosis. Nature 2020;583:425-30.

13. Laman JD, Weller RO. Drainage of cells and soluble antigen from the CNS to regional lymph nodes. J Neuroimmune Pharmacol 2013;8:840-56.

14. Greenhalgh AD, David S, Bennett FC. Immune cell regulation of glia during CNS injury and disease. Nat Rev Neurosci 2020;21:139-52.

15. Aspelund A, Antila S, Proulx ST, et al. A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules. J Exp Med 2015;212:991-9.

16. Prinz M, Priller J. The role of peripheral immune cells in the CNS in steady state and disease. Nat Neurosci 2017;20:136-44.

17. Ginhoux F, Greter M, Leboeuf M, et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 2010;330:841-5.

18. Schulz C, Gomez Perdiguero E, Chorro L, et al. A lineage of myeloid cells independent of Myb and hematopoietic stem cells. Science 2012;336:86-90.

19. Lawson L, Perry V, Dri P, Gordon S. Heterogeneity in the distribution and morphology of microglia in the normal adult mouse brain. Neuroscience 1990;39:151-70.

20. Réu P, Khosravi A, Bernard S, et al. The lifespan and turnover of microglia in the human brain. Cell Rep 2017;20:779-84.

21. Askew K, Li K, Olmos-Alonso A, et al. Coupled proliferation and apoptosis maintain the rapid turnover of microglia in the adult brain. Cell Rep 2017;18:391-405.

22. Lawson L, Perry V, Gordon S. Turnover of resident microglia in the normal adult mouse brain. Neuroscience 1992;48:405-15.

23. Salminen A, Ojala J, Kauppinen A, Kaarniranta K, Suuronen T. Inflammation in Alzheimer’s disease: amyloid-beta oligomers trigger innate immunity defence via pattern recognition receptors. Prog Neurobiol 2009;87:181-94.

24. Kigerl KA, de Rivero Vaccari JP, Dietrich WD, Popovich PG, Keane RW. Pattern recognition receptors and central nervous system repair. Exp Neurol 2014;258:5-16.

25. Neumann H, Takahashi K. Essential role of the microglial triggering receptor expressed on myeloid cells-2 (TREM2) for central nervous tissue immune homeostasis. J Neuroimmunol 2007;184:92-9.

26. Pocock JM, Kettenmann H. Neurotransmitter receptors on microglia. Trends Neurosci 2007;30:527-35.

27. Ribeiro M, Brigas HC, Temido-Ferreira M, et al. Meningeal γδ T cell-derived IL-17 controls synaptic plasticity and short-term memory. Sci Immunol 2019;4:eaay5199.

28. Kipnis J. Multifaceted interactions between adaptive immunity and the central nervous system. Science 2016;353:766-71.

29. Derecki NC, Cardani AN, Yang CH, et al. Regulation of learning and memory by meningeal immunity: a key role for IL-4. J Exp Med 2010;207:1067-80.

30. Eyo UB, Gu N, De S, Dong H, Richardson JR, Wu LJ. Modulation of microglial process convergence toward neuronal dendrites by extracellular calcium. J Neurosci 2015;35:2417-22.

31. Eyo UB, Peng J, Swiatkowski P, Mukherjee A, Bispo A, Wu LJ. Neuronal hyperactivity recruits microglial processes via neuronal NMDA receptors and microglial P2Y12 receptors after status epilepticus. J Neurosci 2014;34:10528-40.

32. Li Y, Du XF, Liu CS, Wen ZL, Du JL. Reciprocal regulation between resting microglial dynamics and neuronal activity in vivo. Dev Cell 2012;23:1189-202.

33. Wake H, Moorhouse AJ, Jinno S, Kohsaka S, Nabekura J. Resting microglia directly monitor the functional state of synapses in vivo and determine the fate of ischemic terminals. J Neurosci 2009;29:3974-80.

34. Tremblay MÈ, Lowery RL, Majewska AK. Microglial interactions with synapses are modulated by visual experience. PLoS Biol 2010;8:e1000527.

35. Madry C, Kyrargyri V, Arancibia-Cárcamo IL, et al. Microglial ramification, surveillance, and interleukin-1β release are regulated by the two-pore domain K+ channel THIK-1. Neuron 2018;97:299-312.e6.

36. Akiyoshi R, Wake H, Kato D, et al. Microglia enhance synapse activity to promote local network synchronization. eNeuro 2018;5:ENEURO.

37. Badimon A, Strasburger HJ, Ayata P, et al. Negative feedback control of neuronal activity by microglia. Nature 2020;586:417-23.

38. Paolicelli RC, Bolasco G, Pagani F, et al. Synaptic pruning by microglia is necessary for normal brain development. Science 2011;333:1456-8.

39. Schafer DP, Lehrman EK, Kautzman AG, et al. Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron 2012;74:691-705.

40. Vainchtein ID, Chin G, Cho FS, et al. Astrocyte-derived interleukin-33 promotes microglial synapse engulfment and neural circuit development. Science 2018;359:1269-73.

41. Wang C, Yue H, Hu Z, et al. Microglia mediate forgetting via complement-dependent synaptic elimination. Science 2020;367:688-94.

42. Weinhard L, di Bartolomei G, Bolasco G, et al. Microglia remodel synapses by presynaptic trogocytosis and spine head filopodia induction. Nat Commun 2018;9:1228.

43. Nguyen PT, Dorman LC, Pan S, et al. Microglial remodeling of the extracellular matrix promotes synapse plasticity. Cell 2020;182:388-403.e15.

44. Miyamoto A, Wake H, Ishikawa AW, et al. Microglia contact induces synapse formation in developing somatosensory cortex. Nat Commun 2016;7:12540.

45. Parkhurst CN, Yang G, Ninan I, et al. Microglia promote learning-dependent synapse formation through brain-derived neurotrophic factor. Cell 2013;155:1596-609.

46. Stevens B, Allen NJ, Vazquez LE, et al. The classical complement cascade mediates CNS synapse elimination. Cell 2007;131:1164-78.

47. Vasek MJ, Garber C, Dorsey D, et al. A complement-microglial axis drives synapse loss during virus-induced memory impairment. Nature 2016;534:538-43.

48. Hong S, Beja-Glasser VF, Nfonoyim BM, et al. Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science 2016;352:712-6.

49. Li Q, Cheng Z, Zhou L, et al. Developmental heterogeneity of microglia and brain myeloid cells revealed by deep single-cell RNA sequencing. Neuron 2019;101:207-223.e10.

50. Nemes-Baran AD, White DR, DeSilva TM. Fractalkine-dependent microglial pruning of viable oligodendrocyte progenitor cells regulates myelination. Cell Rep 2020;32:108047.

51. Hughes AN, Appel B. Microglia phagocytose myelin sheaths to modify developmental myelination. Nat Neurosci 2020;23:1055-66.

52. Gong T, Liu L, Jiang W, Zhou R. DAMP-sensing receptors in sterile inflammation and inflammatory diseases. Nat Rev Immunol 2020;20:95-112.

53. Chen GY, Nuñez G. Sterile inflammation: sensing and reacting to damage. Nat Rev Immunol 2010;10:826-37.

54. Lessard CB, Malnik SL, Zhou Y, et al. High-affinity interactions and signal transduction between Aβ oligomers and TREM2. EMBO Mol Med 2018;10:e9027.

55. Zhao Y, Wu X, Li X, et al. TREM2 is a receptor for β-Amyloid that mediates microglial function. Neuron 2018;97:1023-1031.e7.

56. Yeh FL, Wang Y, Tom I, Gonzalez LC, Sheng M. TREM2 binds to apolipoproteins, including APOE and CLU/APOJ, and thereby facilitates uptake of amyloid-beta by microglia. Neuron 2016;91:328-40.

57. Atagi Y, Liu CC, Painter MM, et al. Apolipoprotein E is a ligand for triggering receptor expressed on myeloid cells 2 (TREM2). J Biol Chem 2015;290:26043-50.

58. Wang Y, Cella M, Mallinson K, et al. TREM2 lipid sensing sustains the microglial response in an Alzheimer’s disease model. Cell 2015;160:1061-71.

59. Daws MR, Sullam PM, Niemi EC, Chen TT, Tchao NK, Seaman WE. Pattern recognition by TREM-2: binding of anionic ligands. J Immunol 2003;171:594-9.

60. Derk J, MacLean M, Juranek J, Schmidt AM. The receptor for advanced glycation endproducts (RAGE) and mediation of inflammatory neurodegeneration. J Alzheimers Dis Parkinsonism 2018;8:421.

61. Qi XM, Ma JF. The role of amyloid beta clearance in cerebral amyloid angiopathy: more potential therapeutic targets. Transl Neurodegener 2017;6:22.

62. Frautschy SA, Yang F, Irrizarry M, et al. Microglial response to amyloid plaques in APPsw transgenic mice. Am J Pathol 1998;152:307-17.

63. Dickson DW, Farlo J, Davies P, Crystal H, Fuld P, Yen SH, et al. Alzheimer’s disease. A double-labeling immunohistochemical study of senile plaques. Am J Pathol 1988;132:86-101.

64. Haga S, Akai K, Ishii T. Demonstration of microglial cells in and around senile (neuritic) plaques in the Alzheimer brain. An immunohistochemical study using a novel monoclonal antibody. Acta Neuropathol 1989;77:569-75.

65. Itagaki S, Mcgeer P, Akiyama H, Zhu S, Selkoe D. Relationship of microglia and astrocytes to amyloid deposits of Alzheimer disease. Journal of Neuroimmunology 1989;24:173-82.

66. Wegiel J, Wisniewski HM. The complex of microglial cells and amyloid star in three-dimensional reconstruction. Acta Neuropathol 1990;81:116-24.

67. Stalder M, Phinney A, Probst A, Sommer B, Staufenbiel M, Jucker M. Association of microglia with amyloid plaques in brains of APP23 transgenic mice. Am J Pathol 1999;154:1673-84.

68. Bolmont T, Haiss F, Eicke D, et al. Dynamics of the microglial/amyloid interaction indicate a role in plaque maintenance. J Neurosci 2008;28:4283-92.

69. Füger P, Hefendehl JK, Veeraraghavalu K, et al. Microglia turnover with aging and in an Alzheimer’s model via long-term in vivo single-cell imaging. Nat Neurosci 2017;20:1371-6.

70. Fuhrmann M, Bittner T, Jung CK, et al. Microglial Cx3cr1 knockout prevents neuron loss in a mouse model of Alzheimer’s disease. Nat Neurosci 2010;13:411-3.

71. Keren-Shaul H, Spinrad A, Weiner A, et al. A unique microglia type associated with restricting development of Alzheimer’s Disease. Cell 2017;169:1276-1290.e17.

72. Mathys H, Adaikkan C, Gao F, et al. Temporal tracking of microglia activation in neurodegeneration at single-cell resolution. Cell Rep 2017;21:366-80.

73. Zhou Y, Song WM, Andhey PS, et al. Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and TREM2-independent cellular responses in Alzheimer’s disease. Nat Med 2020;26:131-42.

74. Grubman A, Chew G, Ouyang JF, et al. A single-cell atlas of entorhinal cortex from individuals with Alzheimer’s disease reveals cell-type-specific gene expression regulation. Nat Neurosci 2019;22:2087-97.

75. Wang Y, Ulland TK, Ulrich JD, et al. TREM2-mediated early microglial response limits diffusion and toxicity of amyloid plaques. J Exp Med 2016;213:667-75.

76. Yuan P, Condello C, Keene CD, et al. TREM2 Haplodeficiency in Mice and Humans Impairs the Microglia Barrier Function Leading to Decreased Amyloid Compaction and Severe Axonal Dystrophy. Neuron 2016;90:724-39.

77. Condello C, Yuan P, Schain A, Grutzendler J. Microglia constitute a barrier that prevents neurotoxic protofibrillar Aβ42 hotspots around plaques. Nat Commun 2015;6:6176.

78. Krabbe G, Halle A, Matyash V, et al. Functional impairment of microglia coincides with Beta-amyloid deposition in mice with Alzheimer-like pathology. PLoS One 2013;8:e60921.

79. Daria A, Colombo A, Llovera G, et al. Young microglia restore amyloid plaque clearance of aged microglia. EMBO J 2017;36:583-603.

80. Grathwohl SA, Kälin RE, Bolmont T, et al. Formation and maintenance of Alzheimer’s disease beta-amyloid plaques in the absence of microglia. Nat Neurosci 2009;12:1361-3.

81. Caldeira C, Cunha C, Vaz AR, et al. Key Aging-Associated Alterations in Primary Microglia Response to Beta-Amyloid Stimulation. Front Aging Neurosci 2017;9:277.

82. Floden AM, Combs CK. Microglia demonstrate age-dependent interaction with amyloid-β fibrils. J Alzheimers Dis 2011;25:279-93.

83. Venegas C, Kumar S, Franklin BS, et al. Microglia-derived ASC specks cross-seed amyloid-β in Alzheimer’s disease. Nature 2017;552:355-61.

84. Mawuenyega KG, Sigurdson W, Ovod V, et al. Decreased clearance of CNS beta-amyloid in Alzheimer’s disease. Science 2010;330:1774.

85. Boche D, Nicoll JA. The role of the immune system in clearance of Abeta from the brain. Brain Pathol 2008;18:267-78.

86. Bard F, Cannon C, Barbour R, et al. Peripherally administered antibodies against amyloid beta-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nat Med 2000;6:916-9.

87. Bacskai BJ, Kajdasz ST, Christie RH, et al. Imaging of amyloid-beta deposits in brains of living mice permits direct observation of clearance of plaques with immunotherapy. Nat Med 2001;7:369-72.

88. Nicoll JA, Wilkinson D, Holmes C, Steart P, Markham H, Weller RO. Neuropathology of human Alzheimer disease after immunization with amyloid-beta peptide: a case report. Nat Med 2003;9:448-52.

89. Nicoll JA, Barton E, Boche D, et al. Abeta species removal after abeta42 immunization. J Neuropathol Exp Neurol 2006;65:1040-8.

90. Schenk D, Barbour R, Dunn W, et al. Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature 1999;400:173-7.

91. Sevigny J, Chiao P, Bussière T, et al. The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease. Nature 2016;537:50-6.

92. Wilcock DM, Rojiani A, Rosenthal A, et al. Passive amyloid immunotherapy clears amyloid and transiently activates microglia in a transgenic mouse model of amyloid deposition. J Neurosci 2004;24:6144-51.

93. Hopp SC, Lin Y, Oakley D, et al. The role of microglia in processing and spreading of bioactive tau seeds in Alzheimer’s disease. J Neuroinflammation 2018;15:269.

94. Asai H, Ikezu S, Tsunoda S, et al. Depletion of microglia and inhibition of exosome synthesis halt tau propagation. Nat Neurosci 2015;18:1584-93.

95. Maphis N, Xu G, Kokiko-Cochran ON, et al. Reactive microglia drive tau pathology and contribute to the spreading of pathological tau in the brain. Brain 2015;138:1738-55.

96. Bolós M, Llorens-Martín M, Jurado-Arjona J, Hernández F, Rábano A, Avila J. Direct Evidence of Internalization of Tau by Microglia In Vitro and In Vivo. J Alzheimers Dis 2016;50:77-87.

97. Mathys H, Davila-Velderrain J, Peng Z, et al. Single-cell transcriptomic analysis of Alzheimer’s disease. Nature 2019;570:332-7.

98. Krasemann S, Madore C, Cialic R, et al. The TREM2-APOE Pathway drives the transcriptional phenotype of dysfunctional microglia in Neurodegenerative Diseases. Immunity 2017;47:566-581.e9.

99. Chen WT, Lu A, Craessaerts K, et al. Spatial transcriptomics and in situ sequencing to study Alzheimer’s Disease. Cell 2020;182:976-991.e19.

100. Carbajosa G, Malki K, Lawless N, et al. Loss of Trem2 in microglia leads to widespread disruption of cell coexpression networks in mouse brain. Neurobiol Aging 2018;69:151-66.

101. Srinivasan K, Friedman BA, Etxeberria A, et al. Alzheimer’s patient microglia exhibit enhanced aging and unique transcriptional activation. Cell Rep 2020;31:107843.

102. El Khoury JB, Moore KJ, Means TK, et al. CD36 mediates the innate host response to beta-amyloid. J Exp Med 2003;197:1657-66.

103. Stewart CR, Stuart LM, Wilkinson K, et al. CD36 ligands promote sterile inflammation through assembly of a Toll-like receptor 4 and 6 heterodimer. Nat Immunol 2010;11:155-61.

104. Sheedy FJ, Grebe A, Rayner KJ, et al. CD36 coordinates NLRP3 inflammasome activation by facilitating intracellular nucleation of soluble ligands into particulate ligands in sterile inflammation. Nat Immunol 2013;14:812-20.

105. Ising C, Venegas C, Zhang S, et al. NLRP3 inflammasome activation drives tau pathology. Nature 2019;575:669-73.

106. Yan SD, Chen X, Fu J, et al. RAGE and amyloid-beta peptide neurotoxicity in Alzheimer’s disease. Nature 1996;382:685-91.

107. Ulland TK, Colonna M. TREM2 - a key player in microglial biology and Alzheimer disease. Nat Rev Neurol 2018;14:667-75.

108. Piers TM, Cosker K, Mallach A, et al. A locked immunometabolic switch underlies TREM2 R47H loss of function in human iPSC-derived microglia. FASEB J 2020;34:2436-50.

109. Zou W, Reeve JL, Liu Y, Teitelbaum SL, Ross FP. DAP12 couples c-Fms activation to the osteoclast cytoskeleton by recruitment of Syk. Mol Cell 2008;31:422-31.

110. Schlepckow K, Monroe KM, Kleinberger G, et al. Enhancing protective microglial activities with a dual function TREM2 antibody to the stalk region. EMBO Mol Med 2020;12:e11227.

111. Takahashi K, Rochford CD, Neumann H. Clearance of apoptotic neurons without inflammation by microglial triggering receptor expressed on myeloid cells-2. J Exp Med 2005;201:647-57.

112. Garcia-Reitboeck P, Phillips A, Piers TM, et al. human induced pluripotent stem cell-derived microglia-like cells harboring TREM2 missense mutations show specific deficits in phagocytosis. Cell Rep 2018;24:2300-11.

113. Xiang X, Werner G, Bohrmann B, et al. TREM2 deficiency reduces the efficacy of immunotherapeutic amyloid clearance. EMBO Mol Med 2016;8:992-1004.

114. Cantoni C, Bollman B, Licastro D, et al. TREM2 regulates microglial cell activation in response to demyelination in vivo. Acta Neuropathol 2015;129:429-47.

115. Kleinberger G, Yamanishi Y, Suárez-Calvet M, et al. TREM2 mutations implicated in neurodegeneration impair cell surface transport and phagocytosis. Sci Transl Med 2014;6:243ra86.

116. Jiang T, Tan L, Zhu XC, et al. Upregulation of TREM2 ameliorates neuropathology and rescues spatial cognitive impairment in a transgenic mouse model of Alzheimer’s disease. Neuropsychopharmacology 2014;39:2949-62.

117. Lee CYD, Daggett A, Gu X, et al. Elevated TREM2 gene dosage reprograms microglia responsivity and ameliorates pathological phenotypes in Alzheimer’s Disease models. Neuron 2018;97:1032-1048.e5.

118. Song WM, Joshita S, Zhou Y, Ulland TK, Gilfillan S, Colonna M. Humanized TREM2 mice reveal microglia-intrinsic and -extrinsic effects of R47H polymorphism. J Exp Med 2018;215:745-60.

119. Wang S, Mustafa M, Yuede CM, et al. Anti-human TREM2 induces microglia proliferation and reduces pathology in an Alzheimer’s disease model. J Exp Med 2020;217:e20200785.

120. Ulrich JD, Finn MB, Wang Y, et al. Altered microglial response to Aβ plaques in APPPS1-21 mice heterozygous for TREM2. Mol Neurodegener 2014;9:20.

121. Cheng-Hathaway PJ, Reed-Geaghan EG, Jay TR, et al. The Trem2 R47H variant confers loss-of-function-like phenotypes in Alzheimer’s disease. Mol Neurodegener 2018;13:29.

122. Ulland TK, Song WM, Huang SC, et al. TREM2 maintains microglial metabolic fitness in Alzheimer’s Disease. Cell 2017;170:649-663.e13.

123. Parhizkar S, Arzberger T, Brendel M, et al. Loss of TREM2 function increases amyloid seeding but reduces plaque-associated ApoE. Nat Neurosci 2019;22:191-204.

124. Jay TR, Miller CM, Cheng PJ, et al. TREM2 deficiency eliminates TREM2+ inflammatory macrophages and ameliorates pathology in Alzheimer’s disease mouse models. J Exp Med 2015;212:287-95.

125. Leyns CEG, Ulrich JD, Finn MB, et al. TREM2 deficiency attenuates neuroinflammation and protects against neurodegeneration in a mouse model of tauopathy. Proc Natl Acad Sci U S A 2017;114:11524-9.

126. Bemiller SM, McCray TJ, Allan K, et al. TREM2 deficiency exacerbates tau pathology through dysregulated kinase signaling in a mouse model of tauopathy. Mol Neurodegener 2017;12:74.

127. Sayed FA, Telpoukhovskaia M, Kodama L, et al. Differential effects of partial and complete loss of TREM2 on microglial injury response and tauopathy. Proc Natl Acad Sci U S A 2018;115:10172-7.

128. Jiang T, Yu JT, Zhu XC, et al. Triggering receptor expressed on myeloid cells 2 knockdown exacerbates aging-related neuroinflammation and cognitive deficiency in senescence-accelerated mouse prone 8 mice. Neurobiol Aging 2014;35:1243-51.

129. Kleinberger G, Brendel M, Mracsko E, et al. The FTD-like syndrome causing TREM2 T66M mutation impairs microglia function, brain perfusion, and glucose metabolism. EMBO J 2017;36:1837-53.

130. Bianchin MM, Capella HM, Chaves DL, et al. Nasu-Hakola Disease (Polycystic Lipomembranous Osteodysplasia with Sclerosing Leukoencephalopathy - PLOSL): A dementia associated with bone cystic lesions. from clinical to genetic and molecular aspects. Cell Mol Neurobiol 2004;24:1-24.

131. Linnartz B, Kopatz J, Tenner AJ, Neumann H. Sialic acid on the neuronal glycocalyx prevents complement C1 binding and complement receptor-3-mediated removal by microglia. J Neurosci 2012;32:946-52.

132. Allendorf DH, Puigdellívol M, Brown GC. Activated microglia desialylate their surface, stimulating complement receptor 3-mediated phagocytosis of neurons. Glia 2020;68:989-98.

133. Gardai SJ, McPhillips KA, Frasch SC, et al. Cell-surface calreticulin initiates clearance of viable or apoptotic cells through trans-activation of LRP on the phagocyte. Cell 2005;123:321-34.

134. Rauch JN, Luna G, Guzman E, et al. LRP1 is a master regulator of tau uptake and spread. Nature 2020;580:381-5.

135. Holtzman DM, Pitas RE, Kilbridge J, et al. Low density lipoprotein receptor-related protein mediates apolipoprotein E-dependent neurite outgrowth in a central nervous system-derived neuronal cell line. Proc Natl Acad Sci U S A 1995;92:9480-4.

136. Fuentealba RA, Liu Q, Zhang J, et al. Low-density lipoprotein receptor-related protein 1 (LRP1) mediates neuronal Abeta42 uptake and lysosomal trafficking. PLoS One 2010;5:e11884.

137. Haure-Mirande JV, Wang M, Audrain M, et al. Integrative approach to sporadic Alzheimer’s disease: deficiency of TYROBP in cerebral Aβ amyloidosis mouse normalizes clinical phenotype and complement subnetwork molecular pathology without reducing Aβ burden. Mol Psychiatry 2019;24:431-46.

138. Zhang B, Gaiteri C, Bodea LG, et al. Integrated systems approach identifies genetic nodes and networks in late-onset Alzheimer’s disease. Cell 2013;153:707-20.

139. Cong Q, Soteros BM, Wollet M, Kim JH, Sia GM. The endogenous neuronal complement inhibitor SRPX2 protects against complement-mediated synapse elimination during development. Nat Neurosci 2020;23:1067-78.

140. O’Brien JS, Sampson EL. Lipid composition of the normal human brain: gray matter, white matter, and myelin. J Lipid Res 1965;6:537-44.

141. Aureli M, Grassi S, Prioni S, Sonnino S, Prinetti A. Lipid membrane domains in the brain. Biochim Biophys Acta 2015;1851:1006-16.

142. Tufail Y, Cook D, Fourgeaud L, et al. Phosphatidylserine exposure controls viral innate immune responses by microglia. Neuron 2017;93:574-586.e8.

143. Lemke G. How macrophages deal with death. Nat Rev Immunol 2019;19:539-49.

144. Cannon JP, O’Driscoll M, Litman GW. Specific lipid recognition is a general feature of CD300 and TREM molecules. Immunogenetics 2012;64:39-47.

145. Shirotani K, Hori Y, Yoshizaki R, et al. Aminophospholipids are signal-transducing TREM2 ligands on apoptotic cells. Sci Rep 2019;9:7508.

146. Fourgeaud L, Través PG, Tufail Y, et al. TAM receptors regulate multiple features of microglial physiology. Nature 2016;532:240-4.

147. Brown GC, Neher JJ. Microglial phagocytosis of live neurons. Nat Rev Neurosci 2014;15:209-16.

148. Andreone BJ, Przybyla L, Llapashtica C, et al. Alzheimer’s-associated PLCγ2 is a signaling node required for both TREM2 function and the inflammatory response in human microglia. Nat Neurosci 2020;23:927-38.

149. Marschallinger J, Iram T, Zardeneta M, et al. Lipid-droplet-accumulating microglia represent a dysfunctional and proinflammatory state in the aging brain. Nat Neurosci 2020;23:194-208.

150. Takeuchi O, Akira S. Pattern recognition receptors and inflammation. Cell 2010;140:805-20.

151. Cunha C, Carvalho A, Esposito A, Bistoni F, Romani L. DAMP signaling in fungal infections and diseases. Front Immunol 2012;3:286.

152. Kumar DK, Choi SH, Washicosky KJ, et al. Amyloid-β peptide protects against microbial infection in mouse and worm models of Alzheimer’s disease. Sci Transl Med 2016;8:340ra72.

153. Eimer WA, Vijaya Kumar DK, Navalpur Shanmugam NK, et al. Alzheimer’s Disease-associated β-Amyloid is rapidly seeded by herpesviridae to protect against brain infection. Neuron 2018;99:56-63.e3.

154. Soscia SJ, Kirby JE, Washicosky KJ, et al. The Alzheimer’s disease-associated amyloid beta-protein is an antimicrobial peptide. PLoS One 2010;5:e9505.

155. Moir RD, Lathe R, Tanzi RE. The antimicrobial protection hypothesis of Alzheimer’s disease. Alzheimers Dement 2018;14:1602-14.

156. Pandey JP, Olsson J, Weidung B, et al. An Ig γ Marker genotype is a strong risk factor for Alzheimer Disease, independent of apolipoprotein E ε4 genotype. J Immunol 2020;205:1318-22.

157. Lövheim H, Gilthorpe J, Adolfsson R, Nilsson LG, Elgh F. Reactivated herpes simplex infection increases the risk of Alzheimer’s disease. Alzheimers Dement 2015;11:593-9.

158. Warren-Gash C, Forbes HJ, Williamson E, et al. Human herpesvirus infections and dementia or mild cognitive impairment: a systematic review and meta-analysis. Sci Rep 2019;9:4743.

159. Readhead B, Haure-Mirande JV, Funk CC, et al. Multiscale analysis of independent alzheimer’s cohorts finds disruption of molecular, genetic, and clinical networks by human herpesvirus. Neuron 2018;99:64-82.e7.

160. Cairns DM, Rouleau N, Parker RN, Walsh KG, Gehrke L, Kaplan DL. A 3D human brain-like tissue model of herpes-induced Alzheimer’s disease. Sci Adv 2020;6:eaay8828.

161. Wozniak MA, Itzhaki RF, Shipley SJ, Dobson CB. Herpes simplex virus infection causes cellular beta-amyloid accumulation and secretase upregulation. Neurosci Lett 2007;429:95-100.

162. McKenzie AT, Wang M, Hauberg ME, et al. Brain cell type specific gene expression and co-expression network architectures. Sci Rep 2018;8:8868.

163. Masuda T, Sankowski R, Staszewski O, Prinz M. Microglia heterogeneity in the single-cell era. Cell Rep 2020;30:1271-81.

164. van der Poel M, Ulas T, Mizee MR, et al. Transcriptional profiling of human microglia reveals grey-white matter heterogeneity and multiple sclerosis-associated changes. Nat Commun 2019;10:1139.

165. Sankowski R, Böttcher C, Masuda T, et al. Mapping microglia states in the human brain through the integration of high-dimensional techniques. Nat Neurosci 2019;22:2098-110.

166. Darmanis S, Sloan SA, Zhang Y, et al. A survey of human brain transcriptome diversity at the single cell level. Proc Natl Acad Sci U S A 2015;112:7285-90.

167. Zhang Y, Sloan SA, Clarke LE, et al. Purification and characterization of progenitor and mature human astrocytes reveals transcriptional and functional differences with mouse. Neuron 2016;89:37-53.

168. Olah M, Patrick E, Villani AC, et al. A transcriptomic atlas of aged human microglia. Nat Commun 2018;9:539.

169. Forabosco P, Ramasamy A, Trabzuni D, et al. Insights into TREM2 biology by network analysis of human brain gene expression data. Neurobiol Aging 2013;34:2699-714.

170. Hawrylycz MJ, Lein ES, Guillozet-Bongaarts AL, et al. An anatomically comprehensive atlas of the adult human brain transcriptome. Nature 2012;489:391-9.

171. Del-Aguila JL, Li Z, Dube U, et al. A single-nuclei RNA sequencing study of Mendelian and sporadic AD in the human brain. Alzheimers Res Ther 2019;11:71.

172. Galatro TF, Holtman IR, Lerario AM, et al. Transcriptomic analysis of purified human cortical microglia reveals age-associated changes. Nat Neurosci 2017;20:1162-71.

173. Mrdjen D, Pavlovic A, Hartmann FJ, et al. High-Dimensional Single-Cell Mapping of Central Nervous System Immune Cells Reveals Distinct Myeloid Subsets in Health, Aging, and Disease. Immunity 2018;48:380-395.e6.

174. Van Hove H, Martens L, Scheyltjens I, et al. A single-cell atlas of mouse brain macrophages reveals unique transcriptional identities shaped by ontogeny and tissue environment. Nat Neurosci 2019;22:1021-35.

175. Jordão MJC, Sankowski R, Brendecke SM, et al. Single-cell profiling identifies myeloid cell subsets with distinct fates during neuroinflammation. Science 2019;363:eaat7554.

176. Zhang Y, Chen K, Sloan SA, 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.

177. Tasic B, Menon V, Nguyen TN, et al. Adult mouse cortical cell taxonomy revealed by single cell transcriptomics. Nat Neurosci 2016;19:335-46.

178. Zeisel A, Muñoz-Manchado AB, Codeluppi S, et al. Brain structure. Cell types in the mouse cortex and hippocampus revealed by single-cell RNA-seq. Science 2015;347:1138-42.

179. Ximerakis M, Lipnick SL, Innes BT, et al. Single-cell transcriptomic profiling of the aging mouse brain. Nat Neurosci 2019;22:1696-708.

180. Hammond TR, Dufort C, Dissing-Olesen L, et al. Single-cell RNA Sequencing of microglia throughout the mouse lifespan and in the injured brain reveals complex cell-state changes. Immunity 2019;50:253-271.e6.

181. Saunders A, Macosko EZ, Wysoker A, et al. Molecular diversity and specializations among the cells of the adult mouse brain. Cell 2018;174:1015-1030.e16.

182. Tay TL, Sagar, Dautzenberg J, Grün D, Prinz M. Unique microglia recovery population revealed by single-cell RNAseq following neurodegeneration. Acta Neuropathol Commun 2018;6:87.

183. Holtman IR, Raj DD, Miller JA, et al. Induction of a common microglia gene expression signature by aging and neurodegenerative conditions: a co-expression meta-analysis. Acta Neuropathol Commun 2015;3:31.

184. Pedersen NL, Gatz M, Berg S, Johansson B. How heritable is Alzheimer’s disease late in life? Findings from Swedish twins. Ann Neurol 2004;55:180-5.

185. Gatz M, Reynolds CA, Fratiglioni L, et al. Role of genes and environments for explaining Alzheimer disease. Arch Gen Psychiatry 2006;63:168-74.

186. Gatz M, Pedersen NL, Berg S, et al. Heritability for Alzheimer’s disease: the study of dementia in Swedish twins. J Gerontol A Biol Sci Med Sci 1997;52:M117-25.

187. Bergem AL, Engedal K, Kringlen E. The role of heredity in late-onset Alzheimer disease and vascular dementia. A twin study. Arch Gen Psychiatry 1997;54:264-70.

188. Corder EH, Saunders AM, Strittmatter WJ, et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 1993;261:921-3.

189. Harold D, Abraham R, Hollingworth P, et al. Erratum: Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer’s disease. Nat Genet 2013;45:712.

190. Lambert JC, Ibrahim-Verbaas CA, Harold D, et al. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease. Nat Genet 2013;45:1452-8.

191. Alzforum. AlzGene - Overview of all published large-scale and genome-wide association studies in AD. Available from: http://www.alzgene.org/largescale.asp. [Last accessed on 29 Jan 2021].

192. Kunkle BW, Grenier-Boley B, Sims R, et al. Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing. Nat Genet 2019;51:414-30.

193. de Rojas I, Moreno-Grau S, Tesi N, et al. Common variants in Alzheimer’s disease: novel association of six genetic variants with AD and risk stratification by polygenic risk scores. medRxiv 2020:19012021.

194. Moreno-Grau S, de Rojas I, Hernández I, et al. Genome-wide association analysis of dementia and its clinical endophenotypes reveal novel loci associated with Alzheimer’s disease and three causality networks: The GR@ACE project. Alzheimers Dement 2019;15:1333-47.

195. Jansen IE, Savage JE, Watanabe K, et al. Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer’s disease risk. Nat Genet 2019;51:404-13.

196. Marioni RE, Harris SE, Zhang Q, et al. GWAS on family history of Alzheimer’s disease. Transl Psychiatry 2018;8:99.

197. Sims R, van der Lee SJ, Naj AC, et al; ARUK Consortium., GERAD/PERADES, CHARGE, ADGC, EADI. Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer’s disease. Nat Genet 2017;49:1373-84.

198. Holstege H, Hulsman M, Charbonnier C, et al. Exome sequencing identifies novel AD-associated genes. medRxiv 2020:20159251.

199. Guerreiro R, Wojtas A, Bras J, et al; Alzheimer Genetic Analysis Group. TREM2 variants in Alzheimer’s disease. N Engl J Med 2013;368:117-27.

200. Jonsson T, Stefansson H, Steinberg S, et al. Variant of TREM2 associated with the risk of Alzheimer’s Disease. N Engl J Med 2013;368:107-16.

201. Fernández MV, Budde J, Del-Aguila JL, et al; NIA-LOAD family study group., NCRAD. Evaluation of Gene-based family-based methods to detect novel genes associated with familial late onset Alzheimer Disease. Front Neurosci 2018;12:209.

202. Nott A, Holtman IR, Coufal NG, et al. Brain cell type-specific enhancer-promoter interactome maps and disease-risk association. Science 2019;366:1134-9.

203. Novikova G, Kapoor M, Julia TCW, et al. Integration of Alzheimer’s disease genetics and myeloid genomics reveals novel disease risk mechanisms. BioRxiv 2019; doi: 10.1101/694281.

204. Amlie-Wolf A, Tang M, Way J, et al. Inferring the molecular mechanisms of noncoding Alzheimer’s Disease-associated genetic variants. J Alzheimers Dis 2019;72:301-18.

205. Jones L, Holmans PA, Hamshere ML, et al. Genetic evidence implicates the immune system and cholesterol metabolism in the aetiology of Alzheimer’s disease. PLoS One 2010;5:e13950.

206. Galatro TF, Vainchtein ID, Brouwer N, Boddeke EWGM, Eggen BJL. Isolation of microglia and immune infiltrates from mouse and primate central nervous system. In: Clausen BE, Laman JD, editors. Inflammation. New York: Springer; 2017. pp. 333-42.

207. Adzhubei IA, Schmidt S, Peshkin L, et al. A method and server for predicting damaging missense mutations. Nat Methods 2010;7:248-9.

208. Vaser R, Adusumalli S, Leng SN, Sikic M, Ng PC. SIFT missense predictions for genomes. Nat Protoc 2016;11:1-9.

209. Ioannidis NM, Rothstein JH, Pejaver V, et al. REVEL: An ensemble method for predicting the pathogenicity of rare missense variants. Am J Hum Genet 2016;99:877-85.

210. Reva B, Antipin Y, Sander C. Predicting the functional impact of protein mutations: application to cancer genomics. Nucleic Acids Res 2011;39:e118.

211. Dong C, Wei P, Jian X, et al. Comparison and integration of deleteriousness prediction methods for nonsynonymous SNVs in whole exome sequencing studies. Hum Mol Genet 2015;24:2125-37.

212. Choi Y, Sims GE, Murphy S, Miller JR, Chan AP. Predicting the functional effect of amino acid substitutions and indels. PLoS One 2012;7:e46688.

213. Park JS, Ji IJ, Kim DH, An HJ, Yoon SY. The Alzheimer’s Disease-associated R47H variant of TREM2 has an altered glycosylation pattern and protein stability. Front Neurosci 2016;10:618.

214. Thornton P, Sevalle J, Deery MJ, et al. TREM2 shedding by cleavage at the H157-S158 bond is accelerated for the Alzheimer’s disease-associated H157Y variant. EMBO Mol Med 2017;9:1366-78.

215. Jiang T, Hou JK, Gao Q, et al. TREM2 p.H157Y variant and the risk of Alzheimer’s Disease: a meta-analysis involving 14,510 subjects. Curr Neurovasc Res 2016;13:318-20.

216. Kober DL, Alexander-Brett JM, Karch CM, et al. Neurodegenerative disease mutations in TREM2 reveal a functional surface and distinct loss-of-function mechanisms. Elife 2016;5:e20391.

217. Sudom A, Talreja S, Danao J, et al. Molecular basis for the loss-of-function effects of the Alzheimer’s disease-associated R47H variant of the immune receptor TREM2. J Biol Chem 2018;293:12634-46.

218. Song W, Hooli B, Mullin K, et al. Alzheimer’s disease-associated TREM2 variants exhibit either decreased or increased ligand-dependent activation. Alzheimers Dement 2017;13:381-7.

219. Paloneva J, Manninen T, Christman G, et al. Mutations in two genes encoding different subunits of a receptor signaling complex result in an identical disease phenotype. Am J Hum Genet 2002;71:656-62.

220. Raj T, Ryan KJ, Replogle JM, et al. CD33: increased inclusion of exon 2 implicates the Ig V-set domain in Alzheimer’s disease susceptibility. Hum Mol Genet 2014;23:2729-36.

221. Estus S, Shaw BC, Devanney N, Katsumata Y, Press EE, Fardo DW. Evaluation of CD33 as a genetic risk factor for Alzheimer’s disease. Acta Neuropathol 2019;138:187-99.

222. Cheng Q, Danao J, Talreja S, et al. TREM2-activating antibodies abrogate the negative pleiotropic effects of the Alzheimer’s disease variant Trem2R47H on murine myeloid cell function. J Biol Chem 2018;293:12620-33.

223. Schlepckow K, Monroe KM, Kleinberger G, et al. Enhancing protective microglial activities with a dual function TREM2 antibody to the stalk region. EMBO Mol Med 2020;12:e11227.

224. Hampe W, Riedel IB, Lintzel J, Bader CO, Franke I, Schaller HC. Ectodomain shedding, translocation and synthesis of SorLA are stimulated by its ligand head activator. J Cell Sci 2000;113:4475-85.

225. Hermey G, Sjøgaard SS, Petersen CM, Nykjaer A, Gliemann J. Tumour necrosis factor alpha-converting enzyme mediates ectodomain shedding of Vps10p-domain receptor family members. Biochem J 2006;395:285-93.

226. Böhm C, Seibel NM, Henkel B, Steiner H, Haass C, Hampe W. SorLA signaling by regulated intramembrane proteolysis. J Biol Chem 2006;281:14547-53.

227. Satoh T, Arii J, Suenaga T, et al. PILRalpha is a herpes simplex virus-1 entry coreceptor that associates with glycoprotein B. Cell 2008;132:935-44.

228. Rathore N, Ramani SR, Pantua H, et al. Paired Immunoglobulin-like Type 2 Receptor Alpha G78R variant alters ligand binding and confers protection to Alzheimer’s disease. PLoS Genet 2018;14:e1007427.

229. Chierico L, Joseph AS, Lewis AL, Battaglia G. Live cell imaging of membrane/cytoskeleton interactions and membrane topology. Sci Rep 2014;4:6056.

230. Lee K, Gallop JL, Rambani K, Kirschner MW. Self-assembly of filopodia-like structures on supported lipid bilayers. Science 2010;329:1341-5.

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

232. Li C, Zhao B, Lin C, Gong Z, An X. TREM2 inhibits inflammatory responses in mouse microglia by suppressing the PI3K/NF-κB signaling. Cell Biol Int 2019;43:360-72.

233. Bernier LP, Bohlen CJ, York EM, et al. Nanoscale surveillance of the brain by microglia via cAMP-regulated filopodia. Cell Rep 2019;27:2895-2908.e4.

234. Heasman SJ, Ridley AJ. Mammalian Rho GTPases: new insights into their functions from in vivo studies. Nat Rev Mol Cell Biol 2008;9:690-701.

235. Ueno T, Falkenburger BH, Pohlmeyer C, Inoue T. Triggering actin comets versus membrane ruffles: distinctive effects of phosphoinositides on actin reorganization. Sci Signal 2011;4:ra87.

236. Oikawa T, Yamaguchi H, Itoh T, et al. PtdIns(3,4,5)P3 binding is necessary for WAVE2-induced formation of lamellipodia. Nat Cell Biol 2004;6:420-6.

237. Phillips AEM, Villegas-Llerena C, Piers TM, Cosker K, Hardy J, Pocock JM. Loss of function of TREM2 results in cytoskeletal malfunction in microglia. J Neurol Neurobiol 2018;4.

238. Cella M, Buonsanti C, Strader C, Kondo T, Salmaggi A, Colonna M. Impaired differentiation of osteoclasts in TREM-2-deficient individuals. J Exp Med 2003;198:645-51.

239. Litschko C, Linkner J, Brühmann S, et al. Differential functions of WAVE regulatory complex subunits in the regulation of actin-driven processes. Eur J Cell Biol 2017;96:715-27.

240. Chen XJ, Squarr AJ, Stephan R, et al. Ena/VASP proteins cooperate with the WAVE complex to regulate the actin cytoskeleton. Dev Cell 2014;30:569-84.

241. Havrylenko S, Noguera P, Abou-Ghali M, et al. WAVE binds Ena/VASP for enhanced Arp2/3 complex-based actin assembly. Mol Biol Cell 2015;26:55-65.

242. Moraes L, Zanchin NIT, Cerutti JM. ABI3, a component of the WAVE2 complex, is potentially regulated by PI3K/AKT pathway. Oncotarget 2017;8:67769-81.

243. Haenseler W, Sansom SN, Buchrieser J, et al. A highly efficient human pluripotent stem cell microglia model displays a neuronal-co-culture-specific expression profile and inflammatory response. Stem Cell Reports 2017;8:1727-42.

244. Buchrieser J, James W, Moore MD. Human induced pluripotent stem cell-derived macrophages share ontogeny with MYB-Independent tissue-resident macrophages. Stem Cell Reports 2017;8:334-45.

245. Abud EM, Ramirez RN, Martinez ES, et al. iPSC-derived human microglia-like cells to study neurological diseases. Neuron 2017;94:278-293.e9.

246. Muffat J, Li Y, Yuan B, et al. Efficient derivation of microglia-like cells from human pluripotent stem cells. Nat Med 2016;22:1358-67.

247. Pandya H, Shen MJ, Ichikawa DM, et al. Differentiation of human and murine induced pluripotent stem cells to microglia-like cells. Nat Neurosci 2017;20:753-9.

248. Takata K, Kozaki T, Lee CZW, et al. Induced-pluripotent-stem-cell-derived primitive macrophages provide a platform for modeling tissue-resident macrophage differentiation and function. Immunity 2017;47:183-198.e6.

249. Brownjohn PW, Smith J, Solanki R, et al. Functional studies of missense TREM2 mutations in human stem cell-derived microglia. Stem Cell Reports 2018;10:1294-307.

250. Hooper C, Taylor DL, Pocock JM. Pure albumin is a potent trigger of calcium signalling and proliferation in microglia but not macrophages or astrocytes. J Neurochem 2005;92:1363-76.

251. Park J, Wetzel I, Marriott I, et al. A 3D human triculture system modeling neurodegeneration and neuroinflammation in Alzheimer’s disease. Nat Neurosci 2018;21:941-51.

Neuroimmunology and Neuroinflammation
ISSN 2349-6142 (Online) 2347-8659 (Print)

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