The Impact of INPP5D on Microglia Response to Tau Pathology in Alzheimer's Disease

Abstract

Alzheimer’s Disease (AD), the most prevalent form of dementia, is neuropathologically defined by the extracellular buildup of amyloid-beta (Aβ) plaques, the formation of intracellular neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau protein, and progressive neuronal degeneration, ultimately leading to cognitive decline. Genetic studies have identified immune-related risk genes linked to AD, underscoring the regulatory role of microglia in AD pathogenesis. Among these genes, INPP5D, which is exclusively expressed by microglia in the brain, has been associated with an increased risk for AD. Elevated INPP5D expression in microglia correlates with amyloid-plaque burden in human AD brain tissue, and studies indicate that INPP5D deficiency modulates amyloid pathology, with effects differing by disease stage and model system. While INPP5D modulation has been shown to impact amyloid pathology, its influence on tau pathology remains largely unexplored. This dissertation seeks to illuminate the role of INPP5D in tau pathogenesis. Our initial studies demonstrated a positive correlation between INPP5D expression and tau-seeding activity in human AD brain samples. Likewise, we observed increased INPP5D expression associated with phospho-tau AT8 levels in PS19 mice, indicating a significant link between INPP5D and tau pathology. Building on these findings, we explored the effect of Inpp5d haplodeficiency on tau pathogenesis in PS19 mice, revealing that Inpp5d haplodeficiency recovered motor functions, mitigated tau pathology, lowered proinflammatory cytokine levels and altered microglial morphology without affecting the overall cellular composition. Transcriptomic analysis also showed the upregulation of genes involved in cell migration, immune response, angiogenesis, and wound healing. These results highlight a complex interplay between Inpp5d, tau pathology, and behavioral outcomes, supporting Inpp5d’s involvement in tau pathogenesis. To explore this further, we treated primary microglia isolated from Wildtype, Inpp5d+/-, and Inpp5d-/- mice with recombinant mutant tau-preformed fibrils and insolubletau extracted from PS19 mice brains. Our results revealed increased tau uptake in Inpp5d+/- and Inpp5d-/- microglia, suggesting that Inpp5d modulation enhances tau uptake, potentially influencing disease progression through altered microglial response. While further research is needed to clarify the mechanisms through which INPP5D influences tau pathogenesis, our findings highlight INPP5D as a promising therapeutic target for modulating tau pathology and improving microglial function in AD.