Promising Alzheimer’s Drug Target Identified by Indiana University Researchers
Scientists at the Indiana University School of Medicine have identified a potential new drug target for Alzheimer’s disease. Their research, published in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, shows that removing a specific enzyme from brain neurons significantly reduces amyloid plaque buildup—a hallmark of the disease—and may enhance the brain’s resilience against further damage. Indiana University School of Medicine
The U.S. Food and Drug Administration has recently approved two disease-modifying drugs for Alzheimer’s disease: lecanemab and donanemab. These treatments work by clearing amyloid plaques from the brain and can help stabilize a person’s current functional state. Indiana University School of Medicine
Targeting the IDOL Enzyme
The research team, led by Hande Karahan, PhD, and Jungsu Kim, PhD, focused on an enzyme called IDOL (indoleamine 2,3-dioxygenase). They discovered that reducing IDOL activity in neurons may offer a novel approach to lowering amyloid levels while simultaneously improving neuronal communication and lipid metabolism. Bloomington Leader
“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 where drugs can attach and block their activity, allowing for precise targeting and minimal side effects.” Bloomington Leader
Unexpected Effects on APOE and Lipid Metabolism
The study utilized two animal models of Alzheimer’s disease, where researchers deleted the IDOL gene from either neurons or microglia (the brain’s immune cells). While initially expecting microglia to play the primary role in plaque clearance, the team observed significant effects when IDOL was removed from neurons. Bloomington Leader
Removing IDOL from neurons reduced amyloid plaques and also lowered levels of apolipoprotein E (APOE), a protein strongly linked to Alzheimer’s disease. The APOE4 variant is the most significant genetic risk factor for late-onset Alzheimer’s. APOE is also crucial for lipid metabolism. Bloomington Leader
Researchers also noted an increase in receptors that regulate both APOE and amyloid plaques when IDOL was removed from neurons. These receptors are vital for lipid metabolism and maintaining healthy neuronal communication. Karahan noted that activating a related pathway has shown promise in protecting against cognitive decline in patients with high plaque levels. Bloomington Leader
“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.” Bloomington Leader
Future Directions in Alzheimer’s Treatment
The research team plans to explore various methods to target IDOL as part of new Alzheimer’s treatments, including testing the safety and effectiveness of potential compounds in preclinical models. They will also investigate whether blocking IDOL can help preserve synaptic connections and reduce tau pathology, another key characteristic of the disease. Indiana University School of Medicine
In related news, the U.S. Food and Drug Administration recently approved the first blood test to detect amyloid plaques associated with Alzheimer’s disease, developed with contributions from an Indiana University School of Medicine researcher. MedBoundTimes
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