TREM2 deficiency eliminates TREM2+ inflammatory macrophages and ameliorates pathology in Alzheimer's disease mouse models.
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.
The Lerner Research Institute and Lou Ruvo Center for Brain Health, Cleveland Clinic, Cleveland, OH 44195 Case Western Reserve University, Cleveland, OH 44106.
Taylor R
TR
Jay
The Lerner Research Institute and Lou Ruvo Center for Brain Health, Cleveland Clinic, Cleveland, OH 44195.
Crystal M
CM
Miller
The Lerner Research Institute and Lou Ruvo Center for Brain Health, Cleveland Clinic, Cleveland, OH 44195 Case Western Reserve University, Cleveland, OH 44106.
Paul J
PJ
Cheng
The Jackson Laboratory, Bar Harbor, ME 04609.
Leah C
LC
Graham
The Lerner Research Institute and Lou Ruvo Center for Brain Health, Cleveland Clinic, Cleveland, OH 44195 Kent State University, Kent, OH 44340.
Shane
S
Bemiller
Case Western Reserve University, Cleveland, OH 44106.
Margaret L
ML
Broihier
The Lerner Research Institute and Lou Ruvo Center for Brain Health, Cleveland Clinic, Cleveland, OH 44195.
Guixiang
G
Xu
The Lerner Research Institute and Lou Ruvo Center for Brain Health, Cleveland Clinic, Cleveland, OH 44195.
Daniel
D
Margevicius
Case Western Reserve University, Cleveland, OH 44106.
J Colleen
JC
Karlo
The Jackson Laboratory, Bar Harbor, ME 04609.
Gregory L
GL
Sousa
The Lerner Research Institute and Lou Ruvo Center for Brain Health, Cleveland Clinic, Cleveland, OH 44195.
Anne C
AC
Cotleur
Brigham and Women's Hospital, Boston, MA 02115.
Oleg
O
Butovsky
The Lerner Research Institute and Lou Ruvo Center for Brain Health, Cleveland Clinic, Cleveland, OH 44195.
Lynn
L
Bekris
The Lerner Research Institute and Lou Ruvo Center for Brain Health, Cleveland Clinic, Cleveland, OH 44195.
Susan M
SM
Staugaitis
The Lerner Research Institute and Lou Ruvo Center for Brain Health, Cleveland Clinic, Cleveland, OH 44195.
James B
JB
Leverenz
The Lerner Research Institute and Lou Ruvo Center for Brain Health, Cleveland Clinic, Cleveland, OH 44195 Case Western Reserve University, Cleveland, OH 44106.
Sanjay W
SW
Pimplikar
Case Western Reserve University, Cleveland, OH 44106.
Gary E
GE
Landreth
The Jackson Laboratory, Bar Harbor, ME 04609.
Gareth R
GR
Howell
The Lerner Research Institute and Lou Ruvo Center for Brain Health, Cleveland Clinic, Cleveland, OH 44195.
Richard M
RM
Ransohoff
The Lerner Research Institute and Lou Ruvo Center for Brain Health, Cleveland Clinic, Cleveland, OH 44195 The Lerner Research Institute and Lou Ruvo Center for Brain Health, Cleveland Clinic, Cleveland, OH 44195 Case Western Reserve University, Cleveland, OH 44106 lambb@ccf.org.
Bruce T
BT
Lamb
D000367:Age Factors; D000368:Aged; D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D006801:Humans; D017493:Leukocyte Common Antigens / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D008822:Mice, Transgenic; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D016875:tau Proteins / Q000378:metabolism
D016229:Amyloid beta-Peptides; C558298:Mapt protein, mouse; D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; C498715:TREM2 protein, human; C498716:Trem2 protein, mouse; D016875:tau Proteins; D017493:Leukocyte Common Antigens