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Neuron. 2016 May 18;90(4):724-39. doi: 10.1016/j.neuron.2016.05.003.

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

Author information

1
Department of Neurology, Yale University, New Haven, CT 06511, USA; Department of Neuroscience, Yale University, New Haven, CT 06511, USA.
2
Department of Neurology, Yale University, New Haven, CT 06511, USA.
3
Department of Pathology, University of Washington, Seattle, WA 98195, USA.
4
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
5
Department of Neurology, University of Washington, Seattle, WA 98195, USA.
6
The Helen and Robert Appel Alzheimer's Disease Research Institute, Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY 10065, USA.
7
Department of Cell Biology, Yale University, New Haven, CT 06511, USA; Nanobiology Institute, Yale University, West Haven, CT 06515, USA.
8
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.

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.

PMID:
27196974
PMCID:
PMC4898967
DOI:
10.1016/j.neuron.2016.05.003
[Indexed for MEDLINE]
Free PMC Article

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