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The Journal of Neuroscience, September 7, 2005, 25(36):8240-8249; doi:10.1523/JNEUROSCI.1808-05.2005

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Neurobiology of Disease
Microglial Phagocytosis Induced by Fibrillar -Amyloid and IgGs Are Differentially Regulated by Proinflammatory Cytokines

Jessica Koenigsknecht-Talboo and Gary E. Landreth

Alzheimer Research Laboratory, Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106

Microglia undergo a phenotypic activation in response to fibrillar -amyloid (fA) 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 fA deposits. However, they can be induced to do so during A vaccination therapy attributable to anti-A antibody stimulation of IgG receptor (FcR)-mediated phagocytic clearance of A plaques.

We report that proinflammatory cytokines attenuate microglial phagocytosis stimulated by fA or complement receptor 3 and argue that this may, in part, underlie the accumulation of fA-containing plaques within the AD brain. The proinflammatory suppression of fA-elicited phagocytosis is dependent on nuclear factor B activation. Significantly, the proinflammatory cytokines do not inhibit phagocytosis elicited by antibody-mediated activation of FcR, which may contribute to the efficiency of A vaccination-based therapy. Importantly, the proinflammatory suppression of fA 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.

Key words: phagocytosis; -amyloid; Alzheimer's disease; NSAIDs; inflammation; cytokines

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Received May 5, 2005; revised July 21, 2005; accepted July 21, 2005.

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