Inpp5d deficiency exacerbates tau pathology and cognitive deficits in MAPTP301S mouse

Abstract

AbstractBackgroundAlzheimer’s disease (AD) is the most common cause of dementia and is characterized by the cerebral accumulation of amyloid plaques and tauopathy. The gene inositol polyphosphate‐5‐phosphatase D (INPP5D), which encodes Src homology 2‐containing‐inositol‐phosphatase‐1 (SHIP1), has been highlighted by multiple approaches as a gene that modulates the risk for AD. SHIP1 expression in brain is restricted to inflammatory cells called microglia that have been shown to play significant roles in the induction and spread of tauopathy. Therefore, the goal of the current study was to examine the effect of microglial Inpp5d/SHIP1 knockdown on a mouse model of tauopathy.MethodWe generated a mouse model of conditional Inpp5d knockdown in microglia to assess the impact on pathology in the MAPTP301S mouse model of tauopathy, using Inpp5dflox mice crossed with an inducible Cx3cr1CreER/+. To induce recombination, 3‐month‐old (mo) Inpp5dfl/fl/Cx3cr1CreER/+ mice, with and without the MAPTP301S transgene, were injected for 5 consecutive days with either tamoxifen (TAM) or corn oil (CO). At 8.5 mo, we assessed learning behavior using the Barnes Maze test and Novel Object Recognition test. Finally, we performed immunohistochemistry, immunoblotting, and quantitative real‐time PCR to assess neuroinflammation and tau pathology.ResultTAM treatment of Inpp5dfl/fl/Cx3cr1CreER/+ mice and MAPTP301S /Inpp5dfl/fl/Cx3cr1CreER/+ mice was used to induce microglial Inpp5d deficiency in both lines. Microglial Inpp5d deficiency in MAPTP301S mice was associated with increased levels of AT8+ hyperphosphorylated tau, yet the numbers of IBA1+ microglia and GFAP+ astrocytes were similar to MAPTP301S expressing normal levels of Inpp5d.ConclusionOur findings suggest that, in our mouse model, Inpp5d deficiency plays an important role in the pathogenesis of tauopathy, but fails to induce an obvious increase in the numbers of either IBA1+ microglia or GFAP+ astrocytes. Our results provide evidence for further evaluation of INPP5D/SHIP1 as a potential target for treating and/or preventing AD.