CD40 signaling regulates innate and adaptive activation of microglia in response to amyloid β-peptide

Although deposition of amyloid beta-peptide (A beta) as A beta plaques involves activation of microglia-mediated inflammatory responses, activated microglia ultimately fail to clear A beta 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 A beta deposition etiologically contributes to AD pathogenesis by promoting A beta plaque formation. However, the mechanisms that govern microglia response in the context of cerebral A beta/beta-amyloid pathology are not well understood. We show that ligation of CD40 by CD40L modulates A beta-induced innate immune responses in microglia, including decreased microglia phagocytosis of exogenous A beta(1-42) and increased production of pro-inflammatory cytokines. CD40 ligation in the presence of A beta(1-42) leads to adaptive activation of microglia, as evidenced by increased colocalization of MHC class II with A beta. To assess their antigen-presenting cell (APC) function, cultured microglia were pulsed with A beta(1-42) in the presence of CD40L and cocultured 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 A beta/beta-amyloid pathology when blocking CD40 signaling in transgenic Alzheimer's mice.