INDIANAPOLIS—Indiana University School of Medicine researchers are studyinghow the reduction of a gene variant found in the brain’s immune cells could diminish the risk of late-onset Alzheimer’s disease.
They focused their investigation on INPP5D, a microglia-specific gene that has been shown to increase the risk for developing late-onset Alzheimer’s disease. Microglia are the brain’s immune cells and there are multiple microglial genes associated with neurodegeneration.
Oblak said the team’s previous data revealed that elevated levels of INPP5D in Alzheimer’s disease lab models resulted in increased plaque deposition. Knowing this, they aimed to understand how reducing expression of INPP5D might regulate disease pathogenesis.
Using models in the lab, the researchers reduced the expression of the gene by at least 50 percent—called haplodeficiency—rather than completely knocking out the expression of the geneto mimic the treatment of pharmacological inhibitors targeting INPP5D as therapeutic strategies.
“INPP5D deficiency increases amyloid uptake and plaque engagement in microglia,” Oblak said. “Furthermore, inhibiting the gene regulates microglial functions and mitigates amyloid pathology that are likely mediated by TREM2-SYK signaling pathway activation.”
The gene deficiency also led to the preservation of cognitive function in the lab models. By reducing the expression of the gene 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 mitigating the function of INPP5D can result in a protective response by diminishing disease risk and mitigating the effect of amyloid beta induced pathogenesis,” Lin said.
The research team is actively working with the IU School of Medicine-Purdue University TaRget Enablement to Accelerate Therapy Development for Alzheimer’s Disease (TREAT-AD) Drug Discovery Center to develop therapies to reduce INPP5D function in Alzheimer’s disease.
IU School of Medicine is the largest medical school in the U.S. and is annually ranked among the top medical schools in the nation by U.S. News & World Report. The school offers high-quality medical education, access to leading medical research and rich campus life in nine Indiana cities, including rural and urban locations consistently recognized for livability.