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THE ROLE OF TREM2 EXPRESSION ON MYELOID CELLS IN ALZHEIMER'S DISEASE
Abstract   Open access   Peer reviewed

THE ROLE OF TREM2 EXPRESSION ON MYELOID CELLS IN ALZHEIMER'S DISEASE

Bruce Lamb, Crystal Miller, Taylor Jay, Leah Graham, Shane Bemiller, Guixiang Xu, Daniel Margevicius, Colleen Karlo, Gregory Sousa, Bunny Cotleur, …
Alzheimer's & dementia, Vol.10(4), pp.P876-P877
07/2014
DOI: 10.1016/j.jalz.2014.07.019
url
https://doi.org/10.1016/j.jalz.2014.07.019View
Published (Version of record) Open Access

Abstract

Background Recent genetic studies implicate inflammatory genes and pathways in the etiology of Alzheimer's disease (AD).Notably, mutations in TREM2, a gene expressed in myeloid cells, were recently demonstrated to confer high risk for developing AD. Mutations in TREM2 have also been identified as the genetic basis of Nasu-Hakola disease, and confer risk for frontotemporal dementia (FTD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS). Since microglia are the primary myeloid cell type within brain, it has been proposed that TREM2 likely functions in AD and other neurodegenerative diseases by modifying microglial function. Methods Here, we assess the cell-type specific expression of TREM2 during the course of AD pathology and in animals lacking TREM2. Results TREM2 was highly expressed in human AD brains, localized mainly in cells surrounding β-amyloid (Aβ) deposits. To define the expression and localization of TREM2 during the time course of Aβ deposition, we examined three different AD mouse models. Quantitative RT-PCR documented significant age-related increases in TREM2 mRNA with corresponding elevations of TREM2 protein in Western blot analyses. Immunohistochemistry confirmed an age-dependent up-regulation of TREM2 around Aβ plaques, as compared to non-transgenic controls. No staining was observed in a Trem2 -/- AD mouse model. Double fluorescent immunohistochemistry and confocal microscopy co-localized TREM2 immunoreactivity within Iba1+ cells surrounding Aβ deposits in APPPS1 mice. These results that were confirmed via in-situ hybridization for TREM2 transcripts and via Xgal staining in a mouse line expressing lacZ under the endogenous Trem2 promoter. The identity of TREM2 expressing cells in AD mouse models was addressed using flow cytometric analysis of CD11b+/CD45 lo microglia and CD11b+/CD45 hi peripheral monocytes. Notably, there was an age-dependent increase in the percentage of TREM2 positive CD11b+/CD45 hi cells in the AD mouse models, while TREM2 expression by CD11b+/CD45 lo cells did not differ from that seen in wild-type animals. Conclusions The current study demonstrates that TREM2 is highly-expressed by plaque-associated myeloid cells in human and animal model AD tissue, but suggests that these TREM2+ cells are macrophages derived from infiltrating peripheral monocytes and not microglia.

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