TREM2 deficiency eliminates TREM2+ inflammatory macrophages and ameliorates pathology in Alzheimer's disease mouse models

The Journal of Experimental Medicine
Taylor R JayBruce T Lamb

Abstract

Variants in triggering receptor expressed on myeloid cells 2 (TREM2) confer high risk for Alzheimer's disease (AD) and other neurodegenerative diseases. However, the cell types and mechanisms underlying TREM2's involvement in neurodegeneration remain to be established. Here, we report that TREM2 is up-regulated on myeloid cells surrounding amyloid deposits in AD mouse models and human AD tissue. TREM2 was detected on CD45(hi)Ly6C(+) myeloid cells, but not on P2RY12(+) parenchymal microglia. In AD mice deficient for TREM2, the CD45(hi)Ly6C(+) macrophages are virtually eliminated, resulting in reduced inflammation and ameliorated amyloid and tau pathologies. These data suggest a functionally important role for TREM2(+) macrophages in AD pathogenesis and an unexpected, detrimental role of TREM2 in AD pathology. These findings have direct implications for future development of TREM2-targeted therapeutics.

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Citations

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Methods Mentioned

BETA
transgenic
Confocal microscopy
flow cytometry
ELISAs
in vitro transcription
PCR
ELISA
FACS

Software Mentioned

Prism
FlowJo
GraphPad
ImageJ
QCapture
SCN Client
Image Pro Plus

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