Amyloid-β induces NLRP1-dependent neuronal pyroptosis in models of Alzheimer’s disease

TLDR

Increasing evidence shows that inflammasome proteins, including NLRP1, are aberrantly expressed in Alzheimer’s disease brain and are linked to inflammatory responses and pyroptotic cell death, yet the specific role of NLRP1 in AD pathogenesis remains unclear. The study aims to determine whether NLRP1 inflammasome contributes to Alzheimer’s disease progression. The authors employed APPswe/PS1dE9 transgenic mice and cultured cortical neurons, measured NLRP1 and caspase‑1 activity, and used non‑viral siRNA to knock down NLRP1 or caspase‑1 to assess effects on neuronal pyroptosis and cognition. They found that NLRP1 and caspase‑1 drive amyloid‑β–induced neuronal pyroptosis, and that silencing these proteins reduces pyroptosis and restores cognitive function, underscoring NLRP1/caspase‑1 as a therapeutic target in AD.

Abstract

Increasing evidence has shown the aberrant expression of inflammasome-related proteins in Alzheimer's disease (AD) brain; these proteins, including NLRP1 inflammasome, are implicated in the execution of inflammatory response and pyroptotic death. Although current data are associated NLRP1 genetic variants with AD, the involvement of NLRP1 inflammasome in AD pathogenesis is still unknown. Using APPswe/PS1dE9 transgenic mice, we found that cerebral NLRP1 levels were upregulated. Our in vitro studies further showed that increased NLRP1-mediated caspase-1-dependent 'pyroptosis' in cultured cortical neurons in response to amyloid-β. Moreover, we employed direct in vivo infusion of non-viral small-interfering RNA to knockdown NLRP1 or caspase-1 in APPswe/PS1dE9 brain, and discovered that these NLRP1 or caspase-1 deficiency mice resulted in significantly reduced neuronal pyroptosis and reversed cognitive impairments. Taken together, our findings indicate an important role for NLRP1/caspase-1 signaling in AD progression, and point to the modulation of NLRP1 inflammasome as a promising strategy for AD therapy.