Microglial Phagocytosis Induced by Fibrillar β-Amyloid and IgGs Are Differentially Regulated by Proinflammatory Cytokines

Abstract

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.

Evaluating the role of Toll-like receptors in diseases of the central nervous system

“…It has been proposed that clearance or deposition of Aβ peptide may be determined by factors such as Aβ peptide burden and the duration of cell exposure [43]. Interestingly it has been reported that proinflammatory cytokines reduces the function of the phagocytic machinery of microglia, which can be relieved by anti-inflammatory cytokines, suggesting a possible strategy for the treatment of AD [45].…”

Attenuation of neuroinflammation and Alzheimer's disease pathology by liver x receptors

“…Microglia are competent phagocytes and normally clear A␤ from the brain (22,43). However, inflammatory cytokines, which are present at elevated levels in the AD brain, suppress the phagocytic activity of these cells.…”

“…Despite decorating amyloid plaques, microglia in the AD brain are poor phagocytes of deposited amyloid. This phenomenon has been proposed to be due in part to inhibition of their phagocytic capacity by the chronic inflammatory milieu (22). Interestingly, antiinflammatory drugs are able to reverse this defect in phagocytosis, suggesting that modulating microglial activation may promote amyloid clearance.…”

Neuroprotective properties of the innate immune system and bone marrow stem cells in Alzheimer's disease

“…Glucocorticoids are crucial for the proper control of an immune response, therefore preventing their production by inhibiting COX-2 can lead to a heightened inflammatory response, especially in the CNS. 91 It has also been recently shown that COX-2 inhibition 92 and prostaglandin E 2 receptor ablation 93 increases b-amyloid phagocytosis by microglial cells, although the mechanisms mediating these actions remain unknown. We must therefore be careful in the interpretation of clinical trials involving the use of NSAIDS for the treatment of neurodegenerative disorders such as AD, since it may in fact be an increased immune response or an increased phagocytic activity in the CNS that is responsible for the protective effects of these drugs.…”