The NLRP3 inflammasome inhibitor OLT1177 rescues cognitive impairment in a mouse model of Alzheimer’s disease
Niklas Lonnemann, Shirin Hosseini, Carlo Marchetti, Damaris B. Skouras, Davide Stefanoni, Angelo D’Alessandro, Charles A. Dinarello, Martin Körte
Abstract
Significance IL-1β is an immunomodulatory cytokine that is overexpressed in the brains of patients with Alzheimer’s disease (AD). The NLRP3 inflammasome is an intracellular complex that activates caspase-1, which processes the IL-1β and IL-18 precursors into active molecules. In this study, we used an APP/PS1 mouse model for AD, which confirms significant cognitive losses that are recovered in NLRP3-deficient mice, to evaluate the therapeutic potential of an orally bioavailable and safe NLRP3 inhibitor, OLT1177. OLT1177 ameliorated the phenotype in APP/PS1 mice, as evidenced by rescued spatial learning and memory in the Morris water maze test. Microglia were less activated, cortical plaques reduced, and plasma AD metabolic markers were normalized. OLT1177 is a potential therapeutic option for AD.