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Pathological Roles of INPP5D in Alzheimer's Disease
Yung Ning Chu1, Aika Akahori1, Sho Takatori1
1Laboratory of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.
Abstract:
Current hypothesis of Alzheimer's disease (AD) postulates that amyloid β (Aβ) deposition in the brain causes tau inclusion in neurons and leads to cognitive decline. The discovery of the genetic association between triggering receptor expressed on myeloid cells 2 (TREM2) with increased AD risk points to a causal link between microglia and AD pathogenesis, and revealed a crucial role of TREM2-dependent clustering of microglia around amyloid plaques that prevents Aβ toxicity to facilitate tau deposition near the plaques. Here we review the physiological and pathological roles of another AD risk gene expressed in microglia, inositol polyphosphate-5-polyphosphatase D (INPP5D), which encodes a phosphoinositide phosphatase. Evidence suggests that its risk polymorphisms alter the expression level and/or function of INPP5D, while concomitantly affecting tau levels in cerebrospinal fluids. In β-amyloidosis mice, INPP5D was upregulated upon Aβ deposition and negatively regulated the microglial clustering toward amyloid plaques. INPP5D seems to exert its function by acting antagonistically at downstream of the TREM2 signaling pathway, suggesting that it is a novel regulator of the protective barrier by microglia. Further studies to elucidate INPP5D's role in AD may help in developing new therapeutic targets for AD treatment.
Insights
Inositol polyphosphate-5-polyphosphatase D (INPP5D) negatively regulates microglial clustering around amyloid plaques, a key process in Alzheimer's disease (AD) pathogenesis. Understanding INPP5D's role may reveal new therapeutic targets for AD.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- Alzheimer's disease (AD) pathogenesis involves amyloid-beta (Aβ) deposition and tau pathology, leading to cognitive decline.
- Genetic links suggest microglia, particularly through TREM2 (triggering receptor expressed on myeloid cells 2), play a critical role in AD.
- TREM2 facilitates microglial clustering around amyloid plaques, forming a protective barrier against Aβ toxicity and influencing tau deposition.
Purpose of the Study:
- To review the roles of inositol polyphosphate-5-phosphatase D (INPP5D), an AD risk gene expressed in microglia.
- To explore INPP5D's function in relation to microglial responses to amyloid plaques and its interaction with TREM2 signaling.
- To identify INPP5D as a potential therapeutic target for Alzheimer's disease.
Main Methods:
- Literature review of studies on INPP5D's physiological and pathological roles in AD.
- Analysis of evidence linking INPP5D risk polymorphisms to altered gene expression and tau levels.
- Examination of INPP5D's effects on microglial clustering in β-amyloidosis mouse models.
Main Results:
- INPP5D is upregulated in response to Aβ deposition in mouse models.
- INPP5D negatively regulates the clustering of microglia around amyloid plaques.
- INPP5D appears to act antagonistically to TREM2 signaling, modulating the microglial protective barrier.
Conclusions:
- INPP5D is a novel regulator of microglial function in the context of Alzheimer's disease.
- Its antagonistic role to TREM2 suggests a complex interplay in AD pathogenesis.
- Further research into INPP5D could lead to new therapeutic strategies for Alzheimer's disease.
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