CD40 signaling regulates innate and adaptive activation of microglia in response to amyloid beta-peptide.
Although deposition of amyloid beta-peptide (Abeta) as Abeta plaques involves activation of microglia-mediated inflammatory responses, activated microglia ultimately fail to clear Abeta plaques in the brains of either Alzheimer's disease (AD) patients or AD mouse models. Mounting evidence suggests that chronic microglia-mediated immune response during Abeta deposition etiologically contributes to AD pathogenesis by promoting Abeta plaque formation. However, the mechanisms that govern microglia response in the context of cerebral Abeta/beta-amyloid pathology are not well understood. We show that ligation of CD40 by CD40L modulates Abeta-induced innate immune responses in microglia, including decreased microglia phagocytosis of exogenous Abeta(1-42) and increased production of pro-inflammatory cytokines. CD40 ligation in the presence of Abeta(1-42) leads to adaptive activation of microglia, as evidenced by increased co-localization of MHC class II with Abeta. To assess their antigen-presenting cell (APC) function, cultured microglia were pulsed with Abeta(1-42) in the presence of CD40L and co-cultured with CD4(+) T cells. Under these conditions, microglia stimulate T cell-derived IFN-gamma and IL-2 production, suggesting that CD40 signaling promotes the APC phenotype. These data provide a mechanistic explanation for our previous work showing decreased microgliosis associated with diminished cerebral Abeta/beta-amyloid pathology when blocking CD40 signaling in transgenic Alzheimer's mice.
Townsend
Kirk P
KP
Neuroimmunology Laboratory, Department of Psychiatry, University of South Florida College of Medicine, Tampa, USA.
Town
Terrence
T
Mori
Takashi
T
Lue
Lih-Fen
LF
Shytle
Doug
D
Sanberg
Paul R
PR
Morgan
David
D
Fernandez
Francisco
F
Flavell
Richard A
RA
Tan
Jun
J
D000544:Alzheimer Disease / Q000276:immunology / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D015153:Blotting, Western; D019013:CD40 Antigens / Q000276:immunology* / Q000378:metabolism; D023201:CD40 Ligand / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005434:Flow Cytometry; D000949:Histocompatibility Antigens Class II / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate; D051379:Mice; D017628:Microglia / Q000276:immunology* / Q000378:metabolism; D008856:Microscopy, Fluorescence; D015398:Signal Transduction / Q000276:immunology*
D016229:Amyloid beta-Peptides; D019013:CD40 Antigens; D000949:Histocompatibility Antigens Class II; D023201:CD40 Ligand