TREM2 lipid sensing sustains the microglial response in an Alzheimer's disease model.
Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial surface receptor that triggers intracellular protein tyrosine phosphorylation. Recent genome-wide association studies have shown that a rare R47H mutation of TREM2 correlates with a substantial increase in the risk of developing Alzheimer's disease (AD). To address the basis for this genetic association, we studied TREM2 deficiency in the 5XFAD mouse model of AD. We found that TREM2 deficiency and haploinsufficiency augment β-amyloid (Aβ) accumulation due to a dysfunctional response of microglia, which fail to cluster around Aβ plaques and become apoptotic. We further demonstrate that TREM2 senses a broad array of anionic and zwitterionic lipids known to associate with fibrillar Aβ in lipid membranes and to be exposed on the surface of damaged neurons. Remarkably, the R47H mutation impairs TREM2 detection of lipid ligands. Thus, TREM2 detects damage-associated lipid patterns associated with neurodegeneration, sustaining the microglial response to Aβ accumulation.
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA; Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.
Yaming
Y
Wang
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Marina
M
Cella
Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA; Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO 63110, USA; Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, USA.
Kaitlin
K
Mallinson
Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA; Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO 63110, USA; Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, USA.
Jason D
JD
Ulrich
Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA; Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO 63110, USA; Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, USA.
Katherine L
KL
Young
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Michelle L
ML
Robinette
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Susan
S
Gilfillan
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Gokul M
GM
Krishnan
Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA; Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO 63110, USA; Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, USA.
Shwetha
S
Sudhakar
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Bernd H
BH
Zinselmeyer
Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA; Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO 63110, USA; Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, USA.
David M
DM
Holtzman
Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA; Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO 63110, USA; Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, USA.
John R
JR
Cirrito
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address: mcolonna@pathology.wustl.edu.
Marco
M
Colonna
D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D002470:Cell Survival; D004195:Disease Models, Animal; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D017628:Microglia / Q000166:cytology / Q000378:metabolism*; D009154:Mutation; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; C498715:TREM2 protein, human; C498716:Trem2 protein, mouse