We have shown that interaction of CD40 with CD40L enables microglial activation in response to amyloid-β peptide (Aβ), which is associated with Alzheimer's disease (AD)-like neuronal tau hyperphosphorylation in vivo. Here we report that transgenic mice overproducing Aβ, but deficient in CD40L, showed decreased astrocytosis and microgliosis associated with diminished Aβ levels and β-amyloid plaque load. Furthermore, in the PSAPP transgenic mouse model of AD, a depleting antibody against CD40L caused marked attenuation of Aβ/β-amyloid pathology, which was associated with decreased amyloidogenic processing of amyloid precursor protein (APP) and increased circulating levels of Aβ. Conversely, in neuroblastoma cells overexpressing wild-type human APP, the CD40–CD40L interaction resulted in amyloidogenic APP processing. These findings suggest several possible mechanisms underlying mitigation of AD pathology in response to CD40L depletion, and validate the CD40–CD40L interaction as a target for therapeutic intervention in AD.