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TREM2 Haplodeficiency in Mice and Humans Impairs the Microglia Barrier Function Leading to Decreased Amyloid Compaction and Severe Axonal Dystrophy.

TitleTREM2 Haplodeficiency in Mice and Humans Impairs the Microglia Barrier Function Leading to Decreased Amyloid Compaction and Severe Axonal Dystrophy.
Publication TypeJournal Article
Year of Publication2016
AuthorsYuan P, Condello C, C Keene D, Wang Y, Bird TD, Paul SM, Luo W, Colonna M, Baddeley D, Grutzendler J
JournalNeuron
Volume90
Issue4
Pagination724-39
Date Published2016 05 18
ISSN1097-4199
KeywordsAlzheimer Disease, Amyloid, Amyloid beta-Peptides, Animals, Axons, Disease Models, Animal, Humans, Membrane Glycoproteins, Mice, Microglia, Mutation, Neurites, Plaque, Amyloid, Receptors, Immunologic
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.

DOI10.1016/j.neuron.2016.05.003
Alternate JournalNeuron
PubMed ID27196974
PubMed Central IDPMC4898967
Grant ListR21 AG048181 / AG / NIA NIH HHS / United States
P50 AG005136 / AG / NIA NIH HHS / United States
R01 NS089734 / NS / NINDS NIH HHS / United States
U24 NS072026 / NS / NINDS NIH HHS / United States
R01 NS089662 / NS / NINDS NIH HHS / United States
P30 AG019610 / AG / NIA NIH HHS / United States
R01 HL106815 / HL / NHLBI NIH HHS / United States
I01 CX001006 / CX / CSRD VA / United States