Wasf1 deletion attenuates tau hyperphosphorylation, microglial state transition, and cognitive deficits in P301S tau mice

Abstract We previously reported that WAVE1, a major activator of Arp2/3 complex-mediated actin polymerization, is downregulated in postmortem brains of Alzheimer’s disease (AD) and that WAVE1 regulates amyloid precursor protein trafficking and amyloid-β production. However, its role in tau pathology remains unknown. Here, we demonstrate that WAVE1 activity is suppressed in P301S tau mice through elevated inhibitory phosphorylation. Strikingly, WAVE1 gene ( Wasf1 ) knockout in P301S tau mice significantly reduces tau hyperphosphorylation and improves cognition, suggesting a compensatory role for WAVE1 suppression in tau pathogenesis. Single-nucleus RNA sequencing reveals that Wasf1 deletion in P301S tau mice reverses microglial state transitions, with minimal impact on other brain cell types. Wasf1 mRNA is highly translated in microglia in non-Tg mice, while its expression is downregulated in P301S tau mice. Wasf1 knockdown in BV2 microglia cells enhances the degradation of engulfed tau fibrils, indicating WAVE1 as an endogenous regulator of microglial function. Additionally, CellChat analysis indicates that Wasf1 deletion alters microglial autocrine signaling and their interactions with other cell types in P301S tau mice. These findings, taken together, suggest that Wasf1 deletion restores homeostatic microglial function, mitigates tau pathology, and alleviates cognitive deficits, highlighting WAVE1 as a potential therapeutic target for tauopathy-related dementias.