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

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 β/β-amyloid pathology when blocking CD40 signaling in transgenic Alzheimer's mice. © 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.