<i>Wasf1</i> deletion attenuates tau hyperphosphorylation, microglial state transition, and cognitive deficits in P301S tau mice

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 ( <i>Wasf1</i> ) 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 <i>Wasf1</i> deletion in P301S tau mice reverses microglial state transitions, with minimal impact on other brain cell types. <i>Wasf1</i> mRNA is highly translated in microglia in non-Tg mice, while its expression is downregulated in P301S tau mice. <i>Wasf1</i> 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 <i>Wasf1</i> deletion alters microglial autocrine signaling and their interactions with other cell types in P301S tau mice. These findings, taken together, suggest that <i>Wasf1</i> deletion restores homeostatic microglial function, mitigates tau pathology, and alleviates cognitive deficits, highlighting WAVE1 as a potential therapeutic target for tauopathy-related dementias.