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

Taylor R Jay; Crystal M Miller; Paul J Cheng; Leah C Graham; Shane Bemiller; Margaret L Broihier; Guixiang Xu; Daniel Margevicius; J Colleen Karlo; Gregory L Sousa; Anne C Cotleur; Oleg Butovsky; Lynn Bekris; Susan M Staugaitis; James B Leverenz; Sanjay W Pimplikar; Gary E Landreth; Gareth R Howell; Richard M Ransohoff; Bruce T Lamb

doi:10.1084/jem.20142322

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

Journal article

Open access

Peer reviewed

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

Taylor R Jay, Crystal M Miller, Paul J Cheng, Leah C Graham, Shane Bemiller, Margaret L Broihier, Guixiang Xu, Daniel Margevicius, J Colleen Karlo, Gregory L Sousa, …

The Journal of experimental medicine, Vol.212(3), pp.287-295

03/09/2015

DOI: 10.1084/jem.20142322

PMCID: PMC4354365

PMID: 25732305

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https://doi.org/10.1084/jem.20142322View

Published (Version of record) Open Access

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.

Age Factors

Aged

Alzheimer Disease - metabolism

Alzheimer Disease - pathology

Amyloid beta-Peptides - metabolism

Animals

Disease Models, Animal

Female

Hippocampus - metabolism

Hippocampus - pathology

Humans

Leukocyte Common Antigens - metabolism

Macrophages - metabolism

Macrophages - pathology

Male

Membrane Glycoproteins - genetics

Membrane Glycoproteins - metabolism

Mice, Transgenic

Receptors, Immunologic - genetics

Receptors, Immunologic - metabolism

tau Proteins - metabolism

Up-Regulation

Details

Title: Subtitle: TREM2 deficiency eliminates TREM2+ inflammatory macrophages and ameliorates pathology in Alzheimer's disease mouse models
Creators: Taylor R Jay - Case Western Reserve University
Crystal M Miller - Cleveland Clinic
Paul J Cheng - Case Western Reserve University
Leah C Graham - Jackson Laboratory
Shane Bemiller - Cleveland Clinic
Margaret L Broihier - Case Western Reserve University
Guixiang Xu - Cleveland Clinic
Daniel Margevicius - Cleveland Clinic
J Colleen Karlo - Case Western Reserve University
Gregory L Sousa - Jackson Laboratory
Anne C Cotleur - Cleveland Clinic
Oleg Butovsky - Brigham and Women's Hospital
Lynn Bekris - Cleveland Clinic
Susan M Staugaitis - Cleveland Clinic
James B Leverenz - Cleveland Clinic
Sanjay W Pimplikar - Case Western Reserve University
Gary E Landreth - Case Western Reserve University
Gareth R Howell - Jackson Laboratory
Richard M Ransohoff - Cleveland Clinic
Bruce T Lamb - Case Western Reserve University
Resource Type: Journal article
Publication Details: The Journal of experimental medicine, Vol.212(3), pp.287-295
DOI: 10.1084/jem.20142322
PMID: 25732305
PMCID: PMC4354365
NLM abbreviation: J Exp Med
ISSN: 0022-1007
eISSN: 1540-9538
Grant note: T32 NS067431 / NINDS NIH HHS T32 GM007250 / NIGMS NIH HHS UL1 TR000439 / NCATS NIH HHS AG023012 / NIA NIH HHS R01 AG023012 / NIA NIH HHS NS047804 / NINDS NIH HHS R01 NS088137 / NINDS NIH HHS NS087298 / NINDS NIH HHS F31 AG048704 / NIA NIH HHS
Language: English
Date published: 03/09/2015
Academic Unit: Iowa Neuroscience Institute; Neuroscience and Pharmacology
Record Identifier: 9985113008002771

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