TREM2-mediated early microglial response limits diffusion and toxicity of amyloid plaques

Yaming Wang, Tyler K. Ulland, Jason D. Ulrich, Wilbur Song, John A. Tzaferis, Justin T. Hole, Peng Yuan, Thomas E. Mahan, Yang Shi, Susan Gilfillan, Marina Cella, Jaime Grutzendler, Ronald B. DeMattos, John R. Cirrito, David M. Holtzman, Marco Colonna

Research output: Contribution to journalArticlepeer-review

351 Scopus citations

Abstract

Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial receptor that recognizes changes in the lipid microenvironment, which may occur during amyloid ß (Aß) accumulation and neuronal degeneration in Alzheimer's disease (AD). Rare TREM2 variants that affect TREM2 function lead to an increased risk of developing AD. In murine models of AD, TREM2 deficiency prevents microglial clustering around Aß deposits. However, the origin of myeloid cells surrounding amyloid and the impact of TREM2 on Aß accumulation are a matter of debate. Using parabiosis, we found that amyloid-associated myeloid cells derive from brain-resident microglia rather than from recruitment of peripheral blood monocytes. To determine the impact of TREM2 deficiency on Aß accumulation, we examined Aß plaques in the 5XFAD model of AD at the onset of Aß-related pathology. At this early time point, Aß accumulation was similar in TREM2-deficient and -sufficient 5XFAD mice. However, in the absence of TREM2, Aß plaques were not fully enclosed by microglia; they were more diffuse, less dense, and were associated with significantly greater neuritic damage. Thus, TREM2 protects from AD by enabling microglia to surround and alter Aß plaque structure, thereby limiting neuritic damage.

Original languageEnglish
Pages (from-to)667-675
Number of pages9
JournalJournal of Experimental Medicine
Volume213
Issue number5
DOIs
StatePublished - May 2 2016

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