The Role of INPP5D in Microglial Function and Amyloid Pathogenesis

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disorder and the most common cause of dementia. Genetic studies implicate the involvement of microglia-mediated immune responses during disease progression. Importantly, inositol polyphosphate-5-phosphatase D (INPP5D) serves as a regulator of microglial functions and its variants have been identified as risk of late-onset AD. The primary object of this thesis was to study the role of INPP5D in AD pathogenesis. First, increased levels of INPP5D were detected in brain regions of LOAD patients, and a positive association was noted between INPP5D expression and amyloid plaque density. Importantly, increased INPP5D expression was also observed in the amyloidogenic 5xFAD mouse model, with a similar pattern of elevated expression predominately in plaque-associated microglia. These results demonstrated that INPP5D plays an important role in AD. Second, we determined the effect of Inpp5d haplodeficiency on amyloid pathology and microglial functions in 5xFAD mice. The results revealed that Inpp5d haploinsufficiency reduced amyloid plaque burdens and reversed behavioral deficits in 5xFAD mice. Inpp5d haploinsufficiency enhanced microglial engagement to plaques while increasing amyloid plaque compaction in the brains. Furthermore, Inpp5d haploinsufficiency activates TREM2 signaling and suppresses proinflammatory cytokines release in cortical tissues. Spatial transcriptomic analysis highlights that Inpp5d haploinsufficiency modulated the functional pathways including immune cell activation, cytokines production, protein degradation, memory, and synaptic plasticity. Our study suggests that reducing INPP5D expression alters microglial responses and mitigates amyloid pathology during AD progression. Finally, we prepared primary microglial cultures from the wild-type and Inpp5d-haplodeficient mice. The microglial cultures were treated with fibrillar beta-amyloid (fAβ) to investigate the effect of INPP5D inhibition on microglial signaling. Our results demonstrate an increased fAβ uptake and decreased fAβ cytotoxicity in the Inpp5d-deficient microglia. Inpp5d haplodeficiency alters microglial functional pathways, including phagocytosis, apoptosis, cytokines production, and the complement system. Importantly, Inpp5d haplodeficiency elevates the expression of homeostatic microglia signatures. Furthermore, treatment of microglia with INPP5D antagonist (TAD32, 1 μM) showed similar effect as the Inpp5d deficiency in microglia. Collectively, our study validates the hypothesis that INPP5D inhibition may help protect against AD pathology. Treatments utilizing INPP5D antagonists to target microglia-mediated immune responses may be beneficial as an AD therapy.