Inpp5d haplodeficiency alleviates tau pathology in the PS19 mouse model of Tauopathy

Abstract INTRODUCTION A noncoding variant (rs35349669) within INPP5D , a lipid and protein phosphatase restricted to microglia in the brain, is linked to increased susceptibility to Alzheimer's disease (AD). While Inpp5d is well‐studied in amyloid pathology, its role in tau pathology remains unclear. METHODS PS19 Tauopathy mice were crossed with Inpp5d‐haplodeficient ( Inpp5d+/− ) mice to examine the impact of Inpp5d in tau pathology. RESULTS Increased INPP5D expression correlated positively with phospho‐Tau AT8 in PS19 mice. Inpp5d haplodeficiency mitigated hyperphosphorylated tau levels (AT8, AT180, AT100, and PHF1) and motor deficits in PS19 mice. Transcriptomic analysis revealed an up‐regulation of genes associated with immune response and cell migration. DISCUSSION Our findings define an association between INPP5D expression and tau pathology in PS19 mice. Alleviation in hyperphosphorylated tau, motor deficits, and transcriptomics changes in haplodeficient‐ Inpp5d PS19 mice indicate that modulation in INPP5D expression may provide therapeutic potential for mitigating tau pathology and improving motor deficits. Highlights The impact of Inpp5d in the context of tau pathology was studied in the PS19 mouse model. INPP5D expression is associated with tau pathology. Reduced Inpp5d expression in PS19 mice improved motor functions and decreased total and phospho‐Tau levels. Inpp5d haplodeficiency in PS19 mice modulates gene expression patterns linked to immune response and cell migration. These data suggest that inhibition of Inpp5d may be a therapeutic approach in tauopathies.