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Alzheimer’s researchers study a gene linked to the brain’s immune cells

Alzheimer’s researchers study a gene linked to the brain’s immune cells

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Summary: Reducing the INPP5D gene variant found in brain microglia may help reduce the risk of late-onset Alzheimer’s disease.

source: Indiana University

Indiana University School of Medicine researchers are investigating how reducing a gene variant found in the brain’s immune cells can reduce the risk of late-onset Alzheimer’s disease.

The research team, led by Adrian Oblak, PhD, Assistant Professor of Radiology and Imaging Sciences, and Peter Bohr-Chian Lin, PhD. candidate in the medical neuroscience master’s program at the Stark Neuroscience Research Institute, recently published their findings in Alzheimer’s and dementia.

They focused their research on INPP5D, a microglia-specific gene that has been shown to increase the risk of developing late-onset Alzheimer’s disease. Microglia are the brain’s immune cells, and there are numerous microglial genes associated with neurodegeneration.

Oblak said the team’s previous data revealed that increased levels of INPP5D in laboratory models of Alzheimer’s disease led to increased plaque deposition. Knowing this, they aimed to understand how downregulation of INPP5D expression might regulate disease pathogenesis.

Using models in the lab, the researchers reduced gene expression by at least 50%—called haplodeficiency—rather than completely knocking out gene expression to mimic treatment with pharmacological inhibitors targeting INPP5D as therapeutic strategies.

Microglia are the brain’s immune cells, and there are numerous microglial genes associated with neurodegeneration. Image is in the public domain

“INPP5D deficiency increases amyloid uptake and plaque engagement in microglia,” Oblak said. “Furthermore, inhibition of the gene regulates microglial functions and attenuates amyloid pathology, which is likely mediated by activation of the TREM2-SYK signaling pathway.”

Gene deficiency also results in preservation of cognitive function in laboratory models. By reducing gene expression in the brain, it creates a less neurotoxic environment and improves the movement of microglia – which act as the first line of defense against viruses, toxic materials and damaged neurons – to clear amyloid deposits and plaques.

“These findings suggest that moderating INPP5D function may lead to a protective response by reducing the risk of disease and mitigating the effect of amyloid beta-induced pathogenesis,” Lin said.

About this Alzheimer’s disease and genetic research news

Author: Press office
source: Indiana University
Contact: Press Office – Indiana University
Image: Image is in the public domain

Original research: Free access.
INPP5D deficiency attenuates amyloid pathology in a mouse model of Alzheimer’s disease” by Peter Bohr-Chian Lin et al. Alzheimer’s and dementia

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Alzheimer’s researchers study a gene linked to the brain’s immune cells

Summary

INPP5D deficiency attenuates amyloid pathology in a mouse model of Alzheimer’s disease

Introduction

Inositol polyphosphate-5-phosphatase (INPP5D) is enriched in microglia lipid phosphatase in the central nervous system. Non-coding variant (rs35349669) c INPP5D increases the risk of Alzheimer’s disease (AD), and increased expression of INPP5D is associated with increased plaque deposition. INPP5D negatively regulates signaling through several microglial cell surface receptors, including triggering receptor expressed on myeloid cells 2 (TREM2); however, the impact of INPP5D inhibition of AD pathology remains unclear.

Methods

We used a 5xFAD mouse model of amyloidosis to assess how Inpp5d haplodeficiency regulates amyloid pathogenesis.

Results

Inpp5d haplodeficiency disrupts microglial intracellular signaling pathways regulating the immune response, including phagocytosis and clearance of amyloid beta (Aβ). It is important to note that Inpp5d haploinsufficiency results in preservation of cognitive function. Spatial transcriptomic analysis revealed that pathways were altered by Inpp5d haploinsufficiency are associated with synaptic regulation and immune cell activation.

Conclusion

This data shows that Inpp5d haplodeficiency improves microglial functions by increasing plaque clearance and preserves cognition in 5xFAD mice. Inhibition of INPP5D is a potential therapeutic strategy for AD.


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