TREM2-mediated early microglial response limits diffusion and toxicity of amyloid plaques.
Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial receptor that recognizes changes in the lipid microenvironment, which may occur during amyloid β (Aβ) accumulation and neuronal degeneration in Alzheimer's disease (AD). Rare TREM2 variants that affect TREM2 function lead to an increased risk of developing AD. In murine models of AD, TREM2 deficiency prevents microglial clustering around Aβ deposits. However, the origin of myeloid cells surrounding amyloid and the impact of TREM2 on Aβ accumulation are a matter of debate. Using parabiosis, we found that amyloid-associated myeloid cells derive from brain-resident microglia rather than from recruitment of peripheral blood monocytes. To determine the impact of TREM2 deficiency on Aβ accumulation, we examined Aβ plaques in the 5XFAD model of AD at the onset of Aβ-related pathology. At this early time point, Aβ accumulation was similar in TREM2-deficient and -sufficient 5XFAD mice. However, in the absence of TREM2, Aβ plaques were not fully enclosed by microglia; they were more diffuse, less dense, and were associated with significantly greater neuritic damage. Thus, TREM2 protects from AD by enabling microglia to surround and alter Aβ plaque structure, thereby limiting neuritic damage.
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110 Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285.
Yaming
Y
Wang
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110.
Tyler K
TK
Ulland
Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110 Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO 63110 Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110.
Jason D
JD
Ulrich
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110.
Wilbur
W
Song
Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285.
John A
JA
Tzaferis
Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285.
Justin T
JT
Hole
Department of Neurology, Yale University, New Haven, CT 06520.
Peng
P
Yuan
Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110 Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO 63110 Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110.
Thomas E
TE
Mahan
Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110 Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO 63110 Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110.
Yang
Y
Shi
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110.
Susan
S
Gilfillan
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110.
Marina
M
Cella
Department of Neurology, Yale University, New Haven, CT 06520.
Jaime
J
Grutzendler
Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285.
Ronald B
RB
DeMattos
Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110 Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO 63110 Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110.
John R
JR
Cirrito
Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110 Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO 63110 Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110.
David M
DM
Holtzman
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110 mcolonna@pathology.wustl.edu holtzman@neuro.wustl.edu.
Marco
M
Colonna
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism* / Q000473:pathology; D009000:Monocytes / Q000378:metabolism / Q000473:pathology; D016501:Neurites / Q000378:metabolism* / Q000473:pathology; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; C498716:Trem2 protein, mouse