Alzheimer’s-prone mice deficient in NLRP3 or caspase-1 fail to develop learning deficits and show reduced neuropathology. Alzheimer's disease is associated with activation of the innate immune system. It is known that amyloid-β can activate the NLRP3 inflammasome in vitro in microglia, and here it is shown that the inflammasome has a critical role in Alzheimer's disease pathology in a mouse model in vivo. In the absence of NLRP3 or caspase-1, amyloidosis and neuropathology in mice is reduced, and cognition and associated electrophysiological parameters improved. Examination of post-mortem human Alzheimer's brains supports the link between NLRP3 and brain inflammation. Taken together, these results suggest that amyloid-β-induced activation of NLRP3 enhances the progression of Alzheimer's disease by mediating a harmful chronic inflammatory tissue post-mortem response, and that agents that block the activity of the NLRP3 inflammasome, or inflammasome-derived cytokines, might slow the progression of Alzheimer's disease. Alzheimer’s disease is the world’s most common dementing illness. Deposition of amyloid-β peptide drives cerebral neuroinflammation by activating microglia1,2. Indeed, amyloid-β activation of the NLRP3 inflammasome in microglia is fundamental for interleukin-1β maturation and subsequent inflammatory events3. However, it remains unknown whether NLRP3 activation contributes to Alzheimer’s disease in vivo. Here we demonstrate strongly enhanced active caspase-1 expression in human mild cognitive impairment and brains with Alzheimer’s disease, suggesting a role for the inflammasome in this neurodegenerative disease. Nlrp3−/− or Casp1−/− mice carrying mutations associated with familial Alzheimer’s disease were largely protected from loss of spatial memory and other sequelae associated with Alzheimer’s disease, and demonstrated reduced brain caspase-1 and interleukin-1β activation as well as enhanced amyloid-β clearance. Furthermore, NLRP3 inflammasome deficiency skewed microglial cells to an M2 phenotype and resulted in the decreased deposition of amyloid-β in the APP/PS1 model of Alzheimer’s disease. These results show an important role for the NLRP3/caspase-1 axis in the pathogenesis of Alzheimer’s disease, and suggest that NLRP3 inflammasome inhibition represents a new therapeutic intervention for the disease.

Microglia are brain-resident myeloid cells that mediate key functions to support the CNS. Microglia express a wide range of receptors that act as molecular sensors, which recognize exogenous or endogenous CNS insults and initiate an immune response. In addition to their classical immune cell function, microglia act as guardians of the brain by promoting phagocytic clearance and providing trophic support to ensure tissue repair and maintain cerebral homeostasis. Conditions associated with loss of homeostasis or tissue changes induce several dynamic microglial processes, including changes of cellular morphology, surface phenotype, secretory mediators, and proliferative responses (referred to as an “activated state”). Activated microglia represent a common pathological feature of several neurodegenerative diseases, including Alzheimer’s disease (AD). Cumulative evidence suggests that microglial inflammatory activity in AD is increased while microglial-mediated clearance mechanisms are compromised. Microglia are perpetually engaged in a mutual interaction with the surrounding environment in CNS; thus, diverse microglial reactions at different disease stages may open new avenues for therapeutic intervention and modification of inflammatory activities. In this Review, the role of microglia in the pathogenesis of AD and the modulation of microglia activity as a therapeutic modality will be discussed.