CoChat
Sign Up
Cited by 21Neuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatmentsDementia and Cognitive Impairment Research

Pathways linking Alzheimer’s disease risk genes expressed highly in microglia

Open access
Hodges, Angela K., Piers, Thomas M., Collier, David, Cousins, Oliver, Pocock, Jennifer M.·2021·Neuroimmunology and Neuroinflammation
DOI 10.20517/2347-8659.2020.60
Open this paper in CoChat — free accountOpen PDF

Abstract

Neuroimmunology and Neuroinflammation is an open access journal, with focuses on neuroimmunology and neuroinflammation research, and coverage extending to other basic and clinical studies related to neuroscience.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.20517/2347-8659.2020.60

Cites

49 of 49 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Biological network analyses of AD loci have consistently implicated both innate and adaptive immune responses as central contributors to AD pathogenesis.

    “Biological network analyses of these loci have consistently implicated both innate and adaptive immune re­ sponses as central contributors to AD pathogenesis.”

    From Is there a role for B cells in Alzheimer's disease? (2026) · cites this paper as [22]

    The Review of genes associated with Alzheimer’s Disease says AD risk genes are over-represented in immune functions, and the Abstract links several to microglial molecular networks. However, THE BRAIN IMMUNE SYSTEM says there is less evidence for direct adaptive-immune activity in the brain; it does not say network analyses consistently implicate both innate and adaptive responses as central contributors to AD pathogenesis. Page numbers are unavailable in our copy. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Other AD risk genes include IL-34, TREM2, CD33, PU.1, and CR1.

    “Other genes include key mediators of microglial activity such as IL-34 , immune receptors including TREM2 and CD33 , transcription factor PU.1, and genes involved in immune processes like complement regulation, including complement receptor 1 ( CR1 ) [22].”

    From Is there a role for B cells in Alzheimer's disease? (2026) · cites this paper as [22]

    The Expression of Alzheimer's Disease Risk Genes in Microglia table (page unavailable) lists IL34, TREM2, CD33, CR1 and SPI1 among AD-associated genes. The Pathways Connecting Alzheimer's Disease Risk Genes in Microglia section identifies TREM2 and CD33 as receptors, and Microglia respond to damage in Alzheimer's disease links CR1 to complement signalling. Our copy does not identify SPI1 as PU.1 or describe PU.1 as a transcription factor, so that part of the attributed list is not verified. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • A substantial proportion of AD-associated risk alleles regulate enhancers specifically in microglia, and approximately 25% of candidate AD risk genes are highly or exclusively expressed by microglia or functionally tied to immune responses.

    “Notably, a sub­ stantial proportion of AD-associated risk alleles have been shown to regulate enhancers specifically in microglia, and approximately 25% of candidate AD risk genes are highly or exclusively expressed by microglia or functionally tied to immune responses [21,22].”

    From Is there a role for B cells in Alzheimer's disease? (2026) · cites this paper as [22]

    The Abstract states that around 25% of approximately 84 AD risk genes have enriched or exclusive expression in microglia and/or are linked to immune function; the Introduction similarly reports 20 of 84 genes with enriched or exclusive microglial expression. The passages found for “enhancer” and microglial regulatory variants do not state that a substantial proportion of AD risk alleles regulate enhancers specifically in microglia, so that part is unsupported by our copy. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 110

  1. Engelhardt B, Vajkoczy P, Weller RO. The movers and shapers in immune privilege of the CNS. Nat Immunol 2017;18:123-31.
  2. 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.
  3. Jeltsch-David H, Muller S. Neuropsychiatric systemic lupus erythematosus: pathogenesis and biomarkers. Nat Rev Neurol 2014;10:579- 96.
  4. 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.
  5. 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.
  6. Boire A, Brastianos PK, Garzia L, Valiente M. Brain metastasis. Nat Rev Cancer 2020;20:4-11.
  7. Forrester JV, McMenamin PG, Dando SJ. CNS infection and immune privilege. Nat Rev Neurosci 2018;19:655-71.
  8. 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.
  9. Montagne A, Zhao Z, Zlokovic BV. Alzheimer's disease: A matter of blood-brain barrier dysfunction? J Exp Med 2017;214:3151-69.
  10. Zlokovic BV. Neurovascular pathways to neurodegeneration in Alzheimer's disease and other disorders. Nat Rev Neurosci 2011;12:723- 38.
  11. Laman JD, Weller RO. Drainage of cells and soluble antigen from the CNS to regional lymph nodes. J Neuroimmune Pharmacol 2013;8:840-56.
  12. Greenhalgh AD, David S, Bennett FC. Immune cell regulation of glia during CNS injury and disease. Nat Rev Neurosci 2020;21:139-52.
  13. 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.
  14. Prinz M, Priller J. The role of peripheral immune cells in the CNS in steady state and disease. Nat Neurosci 2017;20:136-44.
  15. Ginhoux F, Greter M, Leboeuf M, et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 2010;330:841-5.
  16. 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.
  17. 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.
  18. Réu P, Khosravi A, Bernard S, et al. The lifespan and turnover of microglia in the human brain. Cell Rep 2017;20:779-84.
  19. 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.
  20. 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.
  21. Pocock JM, Kettenmann H. Neurotransmitter receptors on microglia. Trends Neurosci 2007;30:527-35.
  22. Kipnis J. Multifaceted interactions between adaptive immunity and the central nervous system. Science 2016;353:766-71.
  23. 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.
  24. 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.
  25. 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.
  26. 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.
  27. Tremblay MÈ, Lowery RL, Majewska AK. Microglial interactions with synapses are modulated by visual experience. PLoS Biol 2010;8:e1000527.
  28. 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.
  29. Badimon A, Strasburger HJ, Ayata P, et al. Negative feedback control of neuronal activity by microglia. Nature 2020;586:417-23.
  30. Paolicelli RC, Bolasco G, Pagani F, et al. Synaptic pruning by microglia is necessary for normal brain development. Science 2011;333:1456-8.
  31. 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.
  32. Wang C, Yue H, Hu Z, et al. Microglia mediate forgetting via complement-dependent synaptic elimination. Science 2020;367:688-94.
  33. 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.
  34. Nguyen PT, Dorman LC, Pan S, et al. Microglial remodeling of the extracellular matrix promotes synapse plasticity. Cell 2020;182:388- 403.e15.
  35. Miyamoto A, Wake H, Ishikawa AW, et al. Microglia contact induces synapse formation in developing somatosensory cortex. Nat Commun 2016;7:12540.
  36. Parkhurst CN, Yang G, Ninan I, et al. Microglia promote learning-dependent synapse formation through brain-derived neurotrophic factor. Cell 2013;155:1596-609.
  37. Stevens B, Allen NJ, Vazquez LE, et al. The classical complement cascade mediates CNS synapse elimination. Cell 2007;131:1164-78.
  38. 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.
  39. Gong T, Liu L, Jiang W, Zhou R. DAMP-sensing receptors in sterile inflammation and inflammatory diseases. Nat Rev Immunol 2020;20:95-112.
  40. Chen GY, Nuñez G. Sterile inflammation: sensing and reacting to damage. Nat Rev Immunol 2010;10:826-37.
  41. 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.
  42. 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.
  43. 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.
  44. 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.
  45. 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.
  46. 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.
  47. Qi XM, Ma JF. The role of amyloid beta clearance in cerebral amyloid angiopathy: more potential therapeutic targets. Transl Neurodegener 2017;6:22.
  48. Frautschy SA, Yang F, Irrizarry M, et al., Microglial response to amyloid plaques in APPsw transgenic mice. Am J Pathol 1998;152:307- 17.
  49. 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.
  50. 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.
  51. Wegiel J, Wisniewski HM. The complex of microglial cells and amyloid star in three-dimensional reconstruction. Acta Neuropathol 1990;81:116-24.
  52. 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.
  53. 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.
  54. 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.
  55. 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.
  56. 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.
  57. 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.
  58. 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.
  59. 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.
  60. 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.
  61. 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.
  62. Floden AM, Combs CK. Microglia demonstrate age-dependent interaction with amyloid-β fibrils. J Alzheimers Dis 2011;25:279-93.
  63. 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.
  64. Mawuenyega KG, Sigurdson W, Ovod V, et al. Decreased clearance of CNS beta-amyloid in Alzheimer's disease. Science 2010;330:1774.
  65. Boche D, Nicoll JA. The role of the immune system in clearance of Abeta from the brain. Brain Pathol 2008;18:267-78.
  66. 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.
  67. 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.
  68. 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.
  69. Nicoll JA, Barton E, Boche D, et al. Abeta species removal after abeta42 immunization. J Neuropathol Exp Neurol 2006;65:1040-8.
  70. 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.
  71. Sevigny J, Chiao P, Bussière T, et al. The antibody aducanumab reduces Aβ plaques in Alzheimer's disease. Nature 2016;537:50-6.
  72. 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.
  73. 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.
  74. 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.
  75. 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.
  76. 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.
  77. Mathys H, Davila-Velderrain J, Peng Z, et al. Single-cell transcriptomic analysis of Alzheimer's disease. Nature 2019;570:332-7.
  78. 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.
  79. 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.
  80. 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.
  81. 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.
  82. 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.
  83. 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.
  84. 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.
  85. 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.
  86. 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.
  87. 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.
  88. 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.
  89. 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.
  90. 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.
  91. 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. 204.
  92. 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.
  93. 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.
  94. 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.
  95. Reva B, Antipin Y, Sander C. Predicting the functional impact of protein mutations: application to cancer genomics. Nucleic Acids Res 2011;39:e118. 211.
  96. 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.
  97. 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.
  98. 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.
  99. 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.
  100. 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.
  101. 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.
  102. 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.
  103. 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.
  104. 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.
  105. 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.
  106. 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.
  107. 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.
  108. 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.
  109. 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.
  110. 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.

Cited by

Sorted by citations

Authors
Hodges, A. K., Piers, T. M., Collier, D., Cousins, O., & Pocock, J. M.
Affiliations
  • King's College London (GB)
  • UCL Queen Square Institute of Neurology (GB)
  • Eli Lilly (United Kingdom) (GB)
Corresponding author
Hodges, Angela K.
ORCID
Venue
Neuroimmunology and Neuroinflammation
Publisher
OAE Publishing Inc.
Published
2021-02-09
Volume
2020
ISSN
  • 2347-8659 (ISSN-L)
  • 2349-6142
DOI
10.20517/2347-8659.2020.60
OpenAlex
W3128480904
Cited by
21
References
49
Citations by year
2026: 3 · 2025: 3 · 2024: 5 · 2023: 7 · 2022: 3
FWCI
1.50
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Neuroimmunology and Neuroinflammation (publishedVersion, cc-by)
  • UCL Discovery (University College London) (submittedVersion)
  • Zenodo (CERN European Organization for Nuclear Research) (submittedVersion, cc-by)
Funders
  • European Federation of Pharmaceutical Industries and Associations
  • European Commission (HORIZON2020, 115976)
  • Innovative Medicines Initiative (115976)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
Alzheimer's disease, risk genes, microglia, gene expression, neuroinflammation, neuroimmunology

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review