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Alzheimer's researchers study gene associated with brain's immune cells

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

Source: indiana university

Researchers at the Indiana University School of Medicine are studying how reducing a genetic variant found in the brain’s immune cells might lower the risk of late-onset Alzheimer’s disease.

The research team, led by Adrian Oblak, Ph.D., assistant professor of radiology and imaging sciences, and Peter Bor-Chian Lin, Ph.D. candidate in the Graduate Program in Medical Neuroscience at the Stark Neurosciences Research Institute, recently published their findings in Alzheimer’s and Dementia.

They focused their investigation 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 several microglial 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 the reduction of INPP5D expression can regulate the pathogenesis of the disease.

Using laboratory models, researchers reduced gene expression by at least 50% – called haplodeficiency – instead of completely eliminating gene expression to mimic the treatment of pharmacological inhibitors targeting INPP5D as therapeutic strategies.

It shows a brain
Microglia are the brain’s immune cells and there are several microglial genes associated with neurodegeneration. The image is in the public domain

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

The genetic deficiency also led to the preservation of cognitive function in the 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 decreasing disease risk and mitigating the effect of beta-amyloid-induced pathogenesis,” said Lin.

About this Alzheimer’s disease and genetic research news

Author: Press office
Source: indiana university
Contact: Press Office – Indiana University
Image: The image is in the public domain

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

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


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


We used the 5xFAD mouse model of amyloidosis to assess how inpp5d Haplodeficiency regulates amyloid pathogenesis.


inpp5d Haplodeficiency disrupts microglial intracellular signaling pathways that regulate the immune response, including phagocytosis and beta-amyloid (Aβ) clearance. It is important to note that inpp5d haploinsufficiency leads to preservation of cognitive function. Spatial transcriptomic analysis revealed that pathways altered by inpp5d haploinsufficiency are related to synaptic regulation and activation of immune cells.


These data demonstrate that inpp5d Haplodeficiency improves microglial functions by increasing plaque clearance and preserves cognitive abilities in 5xFAD mice. INPP5D inhibition is a potential therapeutic strategy for AD.