title: TREM2 Haplodeficiency in Mice and Humans Impairs the Microglia Barrier Function Leading to Decreased Amyloid Compaction and Severe Axonal Dystrophy.
abstract: Haplodeficiency of the microglia gene TREM2 increases risk for late-onset Alzheimer's disease (AD) but the mechanisms remain uncertain. To investigate this, we used high-resolution confocal and super-resolution (STORM) microscopy in AD-like mice and human AD tissue. We found that microglia processes, rich in TREM2, tightly surround early amyloid fibrils and plaques promoting their compaction and insulation. In Trem2- or DAP12-haplodeficient mice and in humans with R47H TREM2 mutations, microglia had a markedly reduced ability to envelop amyloid deposits. This led to an increase in less compact plaques with longer and branched amyloid fibrils resulting in greater surface exposure to adjacent neurites. This was associated with more severe neuritic tau hyperphosphorylation and axonal dystrophy around amyloid deposits. Thus, TREM2 deficiency may disrupt the formation of a neuroprotective microglia barrier that regulates amyloid compaction and insulation. Pharmacological modulation of this barrier could be a novel therapeutic strategy for AD.
authors.affiliation: Department of Neurology, Yale University, New Haven, CT 06511, USA; Department of Neuroscience, Yale University, New Haven, CT 06511, USA.
authors.forename: Peng
authors.initials: P
authors.lastname: Yuan
authors.affiliation: Department of Neurology, Yale University, New Haven, CT 06511, USA.
authors.forename: Carlo
authors.initials: C
authors.lastname: Condello
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA 98195, USA.
authors.forename: C Dirk
authors.initials: CD
authors.lastname: Keene
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Yaming
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Neurology, University of Washington, Seattle, WA 98195, USA.
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Bird
authors.affiliation: The Helen and Robert Appel Alzheimer's Disease Research Institute, Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Paul
authors.affiliation: The Helen and Robert Appel Alzheimer's Disease Research Institute, Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Wenjie
authors.initials: W
authors.lastname: Luo
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Marco
authors.initials: M
authors.lastname: Colonna
authors.affiliation: Department of Cell Biology, Yale University, New Haven, CT 06511, USA; Nanobiology Institute, Yale University, West Haven, CT 06515, USA.
authors.forename: David
authors.initials: D
authors.lastname: Baddeley
authors.affiliation: Department of Neurology, Yale University, New Haven, CT 06511, USA; Department of Neuroscience, Yale University, New Haven, CT 06511, USA. Electronic address: jaime.grutzendler@yale.edu.
authors.forename: Jaime
authors.initials: J
authors.lastname: Grutzendler
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism; D000682:Amyloid / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000235:genetics; D000818:Animals; D001369:Axons / Q000473:pathology*; D004195:Disease Models, Animal; D006801:Humans; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000378:metabolism*; D051379:Mice; D017628:Microglia / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D016501:Neurites / Q000473:pathology; D058225:Plaque, Amyloid / Q000235:genetics / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000172:deficiency / Q000378:metabolism*
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; C498715:TREM2 protein, human; C498716:Trem2 protein, mouse