TitleElevated TREM2 Gene Dosage Reprograms Microglia Responsivity and Ameliorates Pathological Phenotypes in Alzheimer's Disease Models.
Publication TypeJournal Article
Year of Publication2018
AuthorsLee CYDaniel, Daggett A, Gu X, Jiang L-L, Langfelder P, Li X, Wang N, Zhao Y, Park CSin, Cooper Y, Ferando I, Mody I, Coppola G, Xu H, X Yang W
JournalNeuron
Volume97
Issue5
Pagination1032-1048.e5
Date Published2018 Mar 07
ISSN1097-4199
Abstract

Variants of TREM2 are associated with Alzheimer's disease (AD). To study whether increasing TREM2 gene dosage could modify the disease pathogenesis, we developed BAC transgenic mice expressing human TREM2 (BAC-TREM2) in microglia. We found that elevated TREM2 expression reduced amyloid burden in the 5xFAD mouse model. Transcriptomic profiling demonstrated that increasing TREM2 levels conferred a rescuing effect, which includes dampening the expression of multiple disease-associated microglial genes and augmenting downregulated neuronal genes. Interestingly, 5xFAD/BAC-TREM2 mice showed further upregulation of several reactive microglial genes linked to phagocytosis and negative regulation of immune cell activation. Moreover, these mice showed enhanced process ramification and phagocytic marker expression in plaque-associated microglia and reduced neuritic dystrophy. Finally, elevated TREM2 gene dosage led to improved memory performance in AD models. In summary, our study shows that a genomic transgene-driven increase in TREM2 expression reprograms microglia responsivity and ameliorates neuropathological and behavioral deficits in AD mouse models.

DOI10.1016/j.neuron.2018.02.002
Alternate JournalNeuron
PubMed ID29518357
PubMed Central IDPMC5927822
Grant ListR01 NS084298 / NS / NINDS NIH HHS / United States
U01 MH106008 / MH / NIMH NIH HHS / United States
T32 MH073526 / MH / NIMH NIH HHS / United States
R01 AG038710 / AG / NIA NIH HHS / United States
R01 AG021173 / AG / NIA NIH HHS / United States
R21 AG048519 / AG / NIA NIH HHS / United States
R01 AG044420 / AG / NIA NIH HHS / United States
P30 NS062691 / NS / NINDS NIH HHS / United States
RF1 AG056114 / AG / NIA NIH HHS / United States
R01 NS030549 / NS / NINDS NIH HHS / United States
R01 NS074312 / NS / NINDS NIH HHS / United States
R01 NS046673 / NS / NINDS NIH HHS / United States
RF1 AG056130 / AG / NIA NIH HHS / United States