INPP5D modulates TREM2 loss-of-function phenotypes in a β-amyloidosis mouse model
Related Experiment Video
Updated: Aug 3, 2025
Intracerebroventricular Injection of Amyloid-β Peptides in Normal Mice to Acutely Induce Alzheimer-like Cognitive Deficits
Published on: March 16, 2016
Akihiro Iguchi1, Sho Takatori1, Shingo Kimura1
1Laboratory of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
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. Mechanistic analyses suggest that TREM2/TYROBP and INPP5D exert opposing effects on PI(3,4,5)P3 signaling pathways as well as on phosphoproteins involved in the actin assembly. Our results suggest that INPP5D acts downstream of TREM2/TYROBP to regulate the microglial barrier against Aβ toxicity, thereby modulates Aβ-dependent pathological conversion of tau.
Insights
Loss of TREM2 function impairs microglia in Alzheimer disease (AD). Reducing INPP5D in a TREM2 mouse model restored microglial function and reduced AD pathology, revealing INPP5D as a key regulator.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- TREM2 variants are linked to Alzheimer disease (AD), highlighting microglia's protective role.
- TREM2 dysfunction impairs microglial responses to amyloid-beta (Aβ) plaques, worsening AD pathology.
- The precise molecular mechanisms remain unclear.
Purpose of the Study:
- Investigate the role of INPP5D, an AD risk gene, in microglial function and AD pathogenesis.
- Determine how INPP5D interacts with TREM2/TYROBP signaling in a mouse model.
Main Methods:
- Utilized a TREM2 loss-of-function mouse model deficient for TYROBP.
- Introduced Inpp5d haplodeficiency to assess its impact on microglial-plaque interactions and AD pathology.
- Performed mechanistic analyses of signaling pathways and protein phosphorylation.
Main Results:
- Inpp5d haplodeficiency restored microglial association with Aβ plaques and partially improved plaque compaction and astrogliosis.
- Reduced phosphorylated tau-positive dystrophic neurites were observed in Inpp5d-haplodeficient mice.
- TREM2/TYROBP and INPP5D showed opposing effects on PI(3,4,5)P3 signaling and actin assembly pathways.
Conclusions:
- INPP5D acts downstream of TREM2/TYROBP to modulate microglial responses to Aβ.
- INPP5D regulates the microglial barrier against Aβ toxicity and influences tau pathology in AD.
- Targeting INPP5D may offer a therapeutic strategy for Alzheimer disease.
