β-amyloid, microglia, and the inflammasome in Alzheimer's disease

There is extensive evidence that accumulation of mononuclear phagocytes including microglial cells, monocytes, and macrophages at sites of beta-amyloid (A beta) deposition in the brain is an important pathological feature of Alzheimer's disease (AD) and related animal models, and the concentration of these cells clustered around A beta deposits is several folds higher than in neighboring areas of the brain [1-5]. Microglial cells phagocytose and clear debris, pathogens, and toxins, but they can also be activated to produce inflammatory cytokines, chemokines, and neurotoxins [6]. Over the past decade, the roles of microglial cells in AD have begun to be clarified, and we proposed that these cells play a dichotomous role in the pathogenesis of AD [4, 6-11]. Microglial cells are able to clear soluble and fibrillar A beta, but continued interactions of these cells with A beta can lead to an inflammatory response resulting in neurotoxicity. Inflammasomes are inducible high molecular weight protein complexes that are involved in many inflammatory pathological processes. Recently, A beta was found to activate the NLRP3 inflammasome in microglial cells in vitro and in vivo thereby defining a novel pathway that could lead to progression of AD [12-14]. In this manuscript, we review possible steps leading to A beta-induced inflammasome activation and discuss how this could contribute to the pathogenesis of AD.