INDIANAPOLIS — Indiana University School of Medicine scientists have identified a promising drug target for Alzheimer's disease. The team found that removing an enzyme from neurons in the brain substantially reduces amyloid plaques — a hallmark characteristic of the disease — and may provide further resilience against disease progression.
Over the past few years, the U.S. Food and Drug Administration has approved two disease-modifying drugs to treat Alzheimer’s disease. The drugs, lecanemab and donanemab, remove the buildup of amyloid plaques in the brain and can "freeze" a person in their current functional state.
The team of researchers at the IU School of Medicine, led by Hande Karahan, PhD, and Jungsu Kim, PhD, say targeting this enzyme, called IDOL, in neurons can be a new way to remove amyloid plaques and improve communication between neurons and lipid metabolism in the brain.
"What makes this exciting is that we now have a specific target that could lead to a new type of treatment," said Kim, the P. Michael Conneally Professor of Medical and Molecular Genetics. "We believe that IDOL will provide us with an alternative strategy to treat Alzheimer's disease. Targeting enzymes in drug development offers key advantages due to their well-defined active sites or ‘pockets’ where drugs can attach and block their activity. This precision means we can design molecules that hit the right target with minimal side effects."
In the study, published in Alzheimer's & Dementia: The Journal of the Alzheimer's Association, the researchers generated two different animal models of Alzheimer's disease by deleting the IDOL gene in the brain from either within neurons or microglia, the brain’s immune cells.
Karahan, assistant research professor of medical and molecular genetics, said they expected microglia to be the major driver of removing amyloid plaques because immune cells are key players in clearing amyloid and are the main cell type that produces IDOL in the brain.
Deletion of IDOL neurons not only reduced plaques, Karahan said, but it also reduced levels of a protein called apolipoprotein E, or APOE, that is associated with Alzheimer's disease; one of the protein's variants, APOE4, is the strongest risk factor for late-onset Alzheimer's disease. APOE also plays a critical role in lipid metabolism, Karahan said.
The team also discovered that levels of receptors that can regulate APOE and amyloid plaques in the brain increased when the enzyme was removed from neurons. These receptors have a critical role in lipid metabolism and healthy neuronal communication. Karahan said a recent study shows that activating a pathway, which is also regulated by these receptors, provides resilience to cognitive decline in Alzheimer’s patients who have high amounts of plaques.
“This is especially important from a clinical perspective because patients are usually diagnosed with the disease after accumulating substantial amyloid plaque load in the brain. Not only decreasing amyloid levels but also increasing resilience to these pathological changes could maximize clinical benefits,” Karahan said. “Targeting neuronal IDOL may offer multiple therapeutic benefits in Alzheimer’s disease by simultaneously reducing amyloid burden while enhancing neuroprotective effects.”
Kim said the team will next work on a few strategies targeting the enzyme to develop drugs for treating Alzheimer’s disease, adding it’s important to assess the safety of compounds and their functional effects in preclinical models. Kim said they’ll also determine whether IDOL inhibition preserves synaptic connections and mitigates tau pathology in Alzheimer’s disease.
About the Indiana University School of Medicine
The 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. According to the Blue Ridge Institute for Medical Research, the IU School of Medicine ranks No. 13 in 2024 National Institutes of Health funding among all public medical schools in the country.
Writer: Ben Middelkamp bmiddel@iu.edu
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