@article{db92a74b50d64b898f04b55544487eb7,
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.",
author = "Peng Yuan and Carlo Condello and Keene, {C. Dirk} and Yaming Wang and Bird, {Thomas D.} and Paul, {Steven M.} and Wenjie Luo and Marco Colonna and David Baddeley and Jaime Grutzendler",
note = "Funding Information: We thank Lingling Ji (Yale University) for consultation on statistics and Katie N. Murray (Yale University) for critical reading of the manuscript. We thank the University of Washington Alzheimer{\textquoteright}s Disease Research Center Neuropathology Core for provision of human brain tissues (supported by NIA P50 AG05136). We thank Sun Health Research Institute Brain and Body Donation Program of Sun City, Arizona for the provision of human brain tissues, supported by the NINDS (U24 NS072026), the NIA (P30 AG19610), the Arizona Department of Health Services (contract 211002), and the Arizona Biomedical Research Commission (contracts 4001, 0011, 05-901 and 1001). We thank Dennis W. Dickson and Michael Deture at Mayo Clinic (Jacksonville, Florida) for providing additional human brain tissues. We thank the Helen and Robert Appel Alzheimer{\textquoteright}s Disease Research Institute for providing funding; Xiaoyu Hu for providing DAP12 knockout mice; and Mathias Jucker for providing APPPS1-21 mice. This project was supported by R01HL106815 and R21AG048181 (J.G.). This project was supported by National Institute of Health grants R01HL106815 and R21AG048181 (J.G.), and Alzheimer{\textquoteright}s Association Research Grant (J.G.). Publisher Copyright: {\textcopyright} 2016 Elsevier Inc.",
year = "2016",
month = may,
day = "18",
doi = "10.1016/j.neuron.2016.05.003",
language = "English",
volume = "90",
pages = "724--739",
journal = "Neuron",
issn = "0896-6273",
number = "4",
}