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

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Abstract
Although deposition of amyloid β‐peptide (Aβ) as Aβ plaques involves activation of microglia‐mediated inflammatory responses, activated microglia ultimately fail to clear Aβ 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 Aβ deposition etiologically contributes to AD pathogenesis by promoting Aβ plaque formation. However, the mechanisms that govern microglia response in the context of cerebral Aβ/β‐amyloid pathology are not well understood. We show that ligation of CD40 by CD40L modulates Aβ‐induced innate immune responses in microglia, including decreased microglia phagocytosis of exogenous Aβ1–42 and increased production of pro‐inflammatory cytokines. CD40 ligation in the presence of Aβ1–42 leads to adaptive activation of microglia, as evidenced by increased co‐localization of MHC class II with Aβ. To assess their antigen‐presenting cell (APC) function, cultured microglia were pulsed with Aβ1–42 in the presence of CD40L and co‐cultured with CD4+ T cells. Under these conditions, microglia stimulate T cell‐derived IFN‐γ 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 Aβ/β‐amyloid pathology when blocking CD40 signaling in transgenic Alzheimer's mice.