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 Lamb

Research output: Contribution to journalArticle

239 Citations (Scopus)

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 CD45hiLy6C+ myeloid cells, but not on P2RY12+ parenchymal microglia. In AD mice deficient for TREM2, the CD45hiLy6C+ 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.

Original languageEnglish (US)
Pages (from-to)287-295
Number of pages9
JournalJournal of Experimental Medicine
Volume212
Issue number3
DOIs
StatePublished - 2015
Externally publishedYes

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Myeloid Cells
Alzheimer Disease
Macrophages
Pathology
Amyloid Plaques
Microglia
Amyloid
Neurodegenerative Diseases
Inflammation

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

Cite this

TREM2 deficiency eliminates TREM2+ inflammatory macrophages and ameliorates pathology in Alzheimer's disease mouse models. / Jay, Taylor R.; Miller, Crystal M.; Cheng, Paul J.; Graham, Leah C.; Bemiller, Shane; Broihier, Margaret L.; Xu, Guixiang; Margevicius, Daniel; Karlo, J. Colleen; Sousa, Gregory L.; Cotleur, Anne C.; Butovsky, Oleg; Bekris, Lynn; Staugaitis, Susan M.; Leverenz, James B.; Pimplikar, Sanjay W.; Landreth, Gary E.; Howell, Gareth R.; Ransohoff, Richard M.; Lamb, Bruce.

In: Journal of Experimental Medicine, Vol. 212, No. 3, 2015, p. 287-295.

Research output: Contribution to journalArticle

Jay, TR, Miller, CM, Cheng, PJ, Graham, LC, Bemiller, S, Broihier, ML, Xu, G, Margevicius, D, Karlo, JC, Sousa, GL, Cotleur, AC, Butovsky, O, Bekris, L, Staugaitis, SM, Leverenz, JB, Pimplikar, SW, Landreth, GE, Howell, GR, Ransohoff, RM & Lamb, B 2015, 'TREM2 deficiency eliminates TREM2+ inflammatory macrophages and ameliorates pathology in Alzheimer's disease mouse models', Journal of Experimental Medicine, vol. 212, no. 3, pp. 287-295. https://doi.org/10.1084/jem.20142322
Jay, Taylor R. ; Miller, Crystal M. ; Cheng, Paul J. ; Graham, Leah C. ; Bemiller, Shane ; Broihier, Margaret L. ; Xu, Guixiang ; Margevicius, Daniel ; Karlo, J. Colleen ; Sousa, Gregory L. ; Cotleur, Anne C. ; Butovsky, Oleg ; Bekris, Lynn ; Staugaitis, Susan M. ; Leverenz, James B. ; Pimplikar, Sanjay W. ; Landreth, Gary E. ; Howell, Gareth R. ; Ransohoff, Richard M. ; Lamb, Bruce. / TREM2 deficiency eliminates TREM2+ inflammatory macrophages and ameliorates pathology in Alzheimer's disease mouse models. In: Journal of Experimental Medicine. 2015 ; Vol. 212, No. 3. pp. 287-295.
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AU - Howell, Gareth R.

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