Alzheimer's disease: a gene associated with immune cells in the brain

Researchers at Indiana University School of Medicine are studying how to reduce a genetic variant found in brain immune cells that reduces the risk of
late-onset Alzheimer's disease.

The research team, led by Adrian Oblak, Ph.
D.
, assistant professor of radiology and imaging science, and Peter Bor-Chian Lin, a doctoral candidate in the Medical Neuroscience Graduate Program at the Stark Institute for Neuroscience, recently published their findings
in Alzheimer's Disease and Dementia: Journal of the Alzheimer's Association.

They focused their research on INPP5D, a microglia-specific gene that has been shown to increase the risk
of late-onset Alzheimer's disease.
Microglia are immune cells of the brain and have multiple microglia genes involved
in neurodegeneration.

Oblak said the team's previous data showed that elevated levels of INPP5D in laboratory models of Alzheimer's disease led to increased
plaque deposition.
Knowing this, they aimed to understand how a decrease in INPP5D expression regulates the pathogenesis
of the disease.

Using models in the lab, the researchers reduced the expression of the gene by at least 50 percent (called haplodefects), rather than eliminating the expression of the gene altogether to mimic a therapeutic approach that uses a drug inhibitor targeting INPP5D as a therapeutic strategy
.

"INPP5D deficiency increases amyloid uptake and plaque involvement in microglia," Oblak said
.
"In addition, inhibition of this gene regulates microglial function and alleviates amyloid pathology
that may be mediated by activation of the TREM2-SYK signaling pathway.
"

In laboratory models, genetic defects also lead to preservation
of cognitive function.
By reducing the gene's expression in the brain, it creates a less neurotoxic environment and improves the movement of microglia — the first line of defense against viruses, toxic substances and damaged neurons — to remove amyloid deposits and plaques
.

Lin said: "These findings suggest that mitigating the function of INPP5D can produce a protective response
by reducing disease risk and mitigating the impact of amyloid-induced pathogenesis β.
"

The research team is actively collaborating with the Indiana University School of Medicine-Purdue TaRget Enable Center for Accelerated Alzheimer's Disease Treatment Development (treatment-ad) drug discovery to develop treatments
that reduce the function of Alzheimer's disease INPP5D.