NLRP3 INFLAMMASOME INHIBITOR CY-09 ATTENUATES PERIPHERAL INFLAMMATION BUT NOT NEUROINFLAMMATION IN A TRANSGENIC ALZHEIMER’S MOUSE MODEL: A [<SUP>18</SUP>F]DPA-714 PET STUDY

Neuroinflammation (NI) contributes to Alzheimer’s disease (AD) and is exacerbated by peripheral inflammation, although the underlying mechanisms remain unclear. The NLRP3 inflammasome is a promising therapeutic target in AD, but currently available inhibitors show limited brain penetration. In this study, we investigated the impact of selective NLRP3 inhibitor CY-09 on systemically induced inflammation and AD-driven neuroinflammation. APPswePS1dE9 (APP/PS1) transgenic mice (Tg) were used. Four groups of Tg mice received vehicle or CY-09 alone for 5 days or recurrent intraperitoneal lipopolysaccharide (LPS) injections to induce systemic inflammation, followed by 5-day treatment with CY-09 or LPS+vehicle. Neuroinflammation was longitudinally assessed at 6 and 12 months using [¹⁸F]DPA-714 PET imaging, complemented by immunohistochemical analyses. PET imaging revealed a significant increase in neuroinflammation at 6 months following LPS challenge (+15 %), which was reduced by CY-09 treatment. AD-induced neuroinflammation increased progressively with age in vehicle-treated transgenic mice but was not significantly affected by CY-09. Immunohistochemical analyses confirmed these results. Cognitive functions were not affected in any of the groups. Overall, these results indicate that recurrent systemic inflammation accelerates early neuroinflammation in AD mice and that NLRP3 inhibition efficiently blocks peripherally induced neuroinflammation but has limited efficacy against age- and AD-driven neuroinflammation, likely due to the known low brain penetration of CY-09 and/or insufficient treatment duration. These findings support the contribution of peripheral inflammation in accelerating neuroinflammation and of NLRP3 as a therapeutic target in AD, while highlighting the need for inhibitors with improved blood–brain barrier permeability and chronic administration from disease onset.