Project R-17044

Reprogramming Microglial Phagocytosis: The CapZIP regulatory Axis as a druggable Switch to Halt Cognitive Decline (Research)

Age-related cognitive decline represents a major socio-economic burden, and microglial synapse elimination is a key driver of this process. While the microglial actin cytoskeleton orchestrates this pathological phagocytosis, actionable therapeutic targets within this network remain unexploited. We found that DISC1 plays a major role in pathological cytoskeletal remodeling in microglia, and our preliminary data reveal that DISC1 is downregulated in human AD patients. Seeking targetable mediators, our screening in Disc1 LI murine microglia identified CapZIP, a molecular switch regulated by specific kinases, as a critical regulator of microglial actin dynamics. We hypothesize that CapZIP-dependent microglial dysfunction is a primary driver of aberrant synaptic elimination in cognitive decline, and that targeted pharmacological modulation of this axis will restore microglial motility, preserve synaptic integrity, and ultimately rescue cognition. We aim to 1) profile the CapZIP axis by mapping the spatiotemporal dynamics and regulatory network of CapZIP in microglia, 2) conduct a functional in vivo validation of this regulatory network using a fruit fly screening platform, and 3) test whether pharmacological modulation of this axis using an existing drug can rescue cognitive decline in the mammalian Disc1 LI model by normalizing actin cytoskeleton-dependent synapse elimination. In this way, the project elucidates an innovative targetable pathway to revert cognitive decline.

01 November 2026 - 31 October 2030