Summary: Reducing the INPP5D gene variant found in brain microglia may help decrease the risk of late-onset Alzheimer’s disease.
Source: Indiana University
Indiana University School of Medicine researchers are investigating how reducing a genetic variant found in immune cells in the brain could reduce 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-stage Alzheimer’s disease. Microglia are the brain’s immune cells and several microglial genes are associated with neurodegeneration.
Oblak said the team’s previous data found that high levels of INPP5D in laboratory models of Alzheimer’s disease led to increased plaque deposition. Knowing this, they sought to understand how reduced expression of INPP5D might regulate disease pathogenesis.
Using laboratory models, the researchers reduced gene expression by at least 50% – called haplodeficiency – rather than completely suppressing gene expression to mimic the treatment of pharmacological inhibitors targeting INPP5D like therapeutic strategies.
“INPP5D deficiency increases amyloid uptake and plaque engagement in microglia,” Oblak said. “Furthermore, gene inhibition regulates microglial functions and attenuates amyloid pathology which is likely mediated by activation of the TREM2-SYK signaling pathway.”
The genetic deficit also led to the 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 acts as the first line of defense against viruses, toxic materials and damaged neurons – to remove deposits amyloids and plaques.
“These results suggest that attenuation of INPP5D function may elicit a protective response by decreasing disease risk and mitigating the effect of beta-amyloid-induced pathogenesis,” Lin said.
About this Alzheimer’s disease and genetics research news
Author: Press office
Source: Indiana University
Contact: Press Office – Indiana University
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Original research: free access.
“INPP5D deficiency attenuates amyloid pathology in a mouse model of Alzheimer’s diseaseby Peter Bor‐Chian Lin et al. Alzheimer’s and dementia
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Summary
INPP5D deficiency attenuates amyloid pathology in a mouse model of Alzheimer’s disease
Introduction
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 negatively regulates signaling via several microglial cell surface receptors, including trigger receptor expressed on myeloid cells 2 (TREM2); however, the impact of INPP5D inhibition on AD pathology remains unclear.
Methods
We used the 5xFAD mouse model of amyloidosis to assess how Inpp5d haplodeficiency regulates the pathogenesis of amyloid.
Results
Inpp5d Haplodeficiency disrupts intracellular microglial signaling pathways regulating the immune response, including phagocytosis and amyloid beta (Aβ) elimination. It is important to note that Inpp5d haploinsufficiency leads to the preservation of cognitive function. Spatial transcriptomic analysis revealed that the pathways modified by Inpp5d Haploinsufficiency is related to synaptic regulation and immune cell activation.
Conclusion
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.
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