Post-symptomatic NLRP3 inhibition rescues cognitive impairment and mitigates amyloid and tau driven neurodegeneration
Anick Auger, Rania Faidi, Alexis Rickman, Carolina Pena Martinez, Austin Fajfer, Jeremy Carling, Addison Hilyard, Mubashshir Ali, Ryosuke Ono, Connor Cleveland, Ria Seliniotakis, Nhi Truong, Amandine Chefson, Marianne Raymond, Marie-Anne Germain, Michael A. Crackower, Bradlee L. Heckmann
Abstract
Emerging evidence has established neuroinflammation as a primary driver of progressive neuronal loss observed across neurodegenerative diseases (NDDs). The NLRP3 inflammasome is a cytosolic immunoprotective danger sensing complex, which when aberrantly activated drives neuroinflammation, propagates amyloid deposition, and neurodegeneration. Herein, we report the therapeutic benefit of NLRP3 inflammasome inhibition in Alzheimer's disease (AD), using a novel and selective brain-penetrant small molecule NLRP3 inhibitor, VEN-02XX, which we profiled in the 5XFAD/Rubicon KO AD model. We demonstrate for the first time that targeting NLRP3, post-symptomatic establishment, rescues cognitive deficits, mitigates neuronal loss, and is sufficient to significantly reduce reactive microgliosis, neuroinflammation and tau pathology. Our data further suggest that pharmacological inhibition of NLRP3, after disease onset, has the potential to reduce cortical and hippocampal amyloid burden. Together, these results highlight the potential for NLRP3 inhibition as a symptomatic and disease modifying therapeutic target for AD pathology and more broadly NDDs.