Microglia undergo a phenotypic activation in response to fibrillar β-amyloid (fAβ) deposition in the brains of Alzheimer's disease (AD) patients, resulting in their elaboration of inflammatory molecules. Despite the presence of abundant plaque-associated microglia in the brains of AD patients and in animal models of the disease, microglia fail to efficiently clear fAβ deposits. However, they can be induced to do so during Aβ vaccination therapy attributable to anti-Aβ antibody stimulation of IgG receptor (FcR)-mediated phagocytic clearance of Aβ plaques.

We report that proinflammatory cytokines attenuate microglial phagocytosis stimulated by fAβ or complement receptor 3 and argue that this may, in part, underlie the accumulation of fAβ-containing plaques within the AD brain. The proinflammatory suppression of fAβ-elicited phagocytosis is dependent on nuclear factor κB activation. Significantly, the proinflammatory cytokines do not inhibit phagocytosis elicited by antibody-mediated activation of FcR, which may contribute to the efficiency of Aβ vaccination-based therapy. Importantly, the proinflammatory suppression of fAβ phagocytosis can be relieved by the coincubation with anti-inflammatory cytokines, cyclooxygenase inhibitors, ibuprofen, or an E prostanoid receptor antagonist, suggesting that proinflammatory cytokines induce the production of prostaglandins, leading to an E prostanoid receptor-dependent inhibition of phagocytosis. These findings support anti-inflammatory therapies for the treatment of AD.