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

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

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

Source: Indiana University

Indiana University School of Medicine researchers are studying 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 Dr. sc. Adrian Oblak, assistant professor of radiology and imaging sciences, and Ph.D. Peter Bor-Chian Lin. candidate in the medical neuroscience graduate program at the Stark Institute for Neuroscience Research, recently published their findings in Alzheimer’s disease 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 immune cells of the brain and there are multiple microglia genes associated with neurodegeneration.

Oblak said the team’s previous data revealed that elevated levels of INPP5D in laboratory models of Alzheimer’s disease resulted in increased plaque deposition. Knowing this, they sought to understand how downregulation of INPP5D expression could 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 that target INPP5D as a therapeutic strategy.

Microglia are the immune cells of the brain and there are multiple microglia genes associated with neurodegeneration. The image is in the public domain

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

Lack of the gene also led to preservation of cognitive function in laboratory models. By reducing gene expression in the brain, it created a less neurotoxic environment and improved 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 attenuating INPP5D function may result in a protective response by reducing disease risk 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
Picture: The image is in the public domain

Original research: Open access.
INPP5D deficiency reduces amyloid pathology in a mouse model of Alzheimer’s disease” by Peter Bor‐Chian Lin et al. Alzheimer’s disease and dementia

See also

This shows the outline of the brain

Abstract

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

Introduction

Inositol polyphosphate-5-phosphatase (INPP5D) is a lipid phosphatase enriched in microglia in the central nervous system. Variant without coding (rs35349669) in INPP5D increases the risk for Alzheimer’s disease (AD), and elevated INPP5D expression is associated with increased plaque deposition. INPP5D negatively regulates signaling through several microglial cell surface receptors, including the trigger receptor expressed on myeloid cells 2 (TREM2); however, the influence of INPP5D inhibition of AD pathology remains unclear.

Methods

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

the results

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

Conclusion

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



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