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

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.

• Authors: 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
• Journal: The Journal of experimental medicine (J Exp Med) Vol. 212 Issue 3 Pg. 287-95 (Mar 09 2015) ISSN: 1540-9538 [Electronic] United States
• PMID: 25732305 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: © 2015 Jay et al.

Chemical References

• Amyloid beta-Peptides
• Mapt protein, mouse
• Membrane Glycoproteins
• Receptors, Immunologic
• TREM2 protein, human
• Trem2 protein, mouse
• tau Proteins
• Leukocyte Common Antigens

Topics

• Age Factors
• Aged
• Alzheimer Disease (metabolism, pathology)
• Amyloid beta-Peptides (metabolism)
• Animals
• Disease Models, Animal
• Female
• Hippocampus (metabolism, pathology)
• Humans
• Leukocyte Common Antigens (metabolism)
• Macrophages (metabolism, pathology)
• Male
• Membrane Glycoproteins (genetics, metabolism)
• Mice, Transgenic
• Receptors, Immunologic (genetics, metabolism)
• Up-Regulation
• tau Proteins (metabolism)