INPP5D Modulates TREM2 Loss-of-Function Phenotypes in a Mouse Model of Alzheimer Disease

Abstract

The genetic associations of TREM2 loss-of-function variants with Alzheimer disease (AD) indicate the protective roles of microglia in AD pathogenesis. Functional deficiencies of TREM2 disrupt microglial clustering around amyloid β (Aβ) plaques, impair their transcriptional response to Aβ, and worsen neuritic dystrophy. However, the molecular mechanism underlying these phenotypes remains unclear. In this study, we investigated the pathological role of another AD risk gene, INPP5D, encoding a phosphoinositide PI(3,4,5)P₃ phosphatase expressed in microglia. In a Tyrobp-deficient  TREM2 loss-of-function mouse model, Inpp5d haplodeficiency restored the association of microglia with Aβ plaques, partially restored plaque compaction and astrogliosis, and reduced phosphorylated tau⁺ dystrophic neurites. RNA-sequencing of isolated microglia demonstrated that the expression of “disease-associated microglia” genes is not responsible for these beneficial effects. Our results suggest that INPP5D acts downstream of TREM2/TYROBP to regulate the microglial barrier against Aβ toxicity, thereby modulates the pathological progression from Aβ deposition to tau pathology.

Keywords: Alzheimer disease, amyloid-β peptide, inositol polyphosphate-5-phosphatase D, microglia, microtubule-associated protein tau, phosphoinositide, triggering receptor expressed on myeloid cells 2, TYRO protein tyrosine kinase-binding protein