NLRP3 inflammasome activation in Alzheimer's disease (INC9P.446)

Abstract

Abstract Neuroinflammation is now recognized as a fundamental response in Alzheimer’s pathology. Prominent activation of inflammatory responses has been observed in the brains of patients with Alzheimer’s disease, as well as in mouse models, however the role of neuroinflammation in Alzheimer’s disease pathogenesis is still not clear. We have reported that the fibrillar form of beta amyloid is capable of stimulating the production of the inflammatory cytokine IL-1β from microglia cells through the activation of the NLRP3 inflammasome. NLRP3 mediated IL-1β production, in turn, induced neurotoxic factors from microglia cells and resulted in neuronal cell death. More importantly, we have recently bred the APP/PS1 mouse into the NLRP3 knock out mice and showed that NLRP3 deficient APP/PS1 mice were completely protected from learning and memory deficits and had decreased Amyloid beta plaques. NLRP3 activation induces both IL-1β and IL18 production. However the role of IL-1β or IL-18, both downstream of NLRP3 inflammasomes, in neuronal cell death are not clear. We used microglia cells and mouse neuronal cell line co-culture system to show the increased neuronal cell death was dependent on the activation of caspase-1 when stimulating microglia cells with Amyloid beta. In addition, IL-1β or IL-18 have synergistic effect in inducing neuronal cell death.