Researchers at Indiana University School of Medicine have identified a new potential way to treat Alzheimer’s disease by targeting an enzyme in the brain called IDOL. Laboratory studies have shown that removing the enzyme from neurons significantly reduces amyloid plaques, one of the main biological hallmarks of Alzheimer’s disease, and may also increase the brain’s resistance to damage associated with the disease.
The discovery comes as scientists continue to search for improved treatments for Alzheimer’s disease. In recent years, the U.S. Food and Drug Administration has approved two disease-modifying drugs, lecanemab and donanemab, that work by clearing the buildup of amyloid plaques in the brain. These treatments help stabilize the patient’s condition by slowing further decline.
The Indiana University team believes that targeting IDOL may provide a different strategy to fight Alzheimer’s disease while improving communication between brain cells and supporting healthy lipid metabolism.
“What makes this interesting is that we found a specific target that could lead to a new type of therapy,” said Kim, the P. Michael Conniely Professor of Molecular Genetics in Medicine. “We believe that IDOL offers an alternative strategy to treat Alzheimer’s disease. Targeting enzymes in drug development offers important advantages because they have well-defined active sites, or ‘pockets’ where the drug can bind and block its activity.” This precision means that molecules can be designed to attack the right target while minimizing side effects. ”
Brain cell experiments reveal surprising results
The survey results are Alzheimer’s Disease and Dementia: Journal of the Alzheimer’s Association. The researchers created two separate animal models of Alzheimer’s disease by deleting the IDOL gene in different types of brain cells, including neurons and microglia, which are immune cells in the brain.
Scientists initially expected microglia to play a larger role in clearing amyloid plaques. This is because these immune cells help remove harmful substances from the brain and are the main producers of IDOL.
Instead, the most pronounced effects appeared when IDOL was removed from neurons.
Dr. Hande Karahan, assistant professor of medicine and molecular genetics, said that deleting IDOL in neurons not only reduces plaque levels, but also reduces levels of apolipoprotein E (APOE), a protein strongly associated with Alzheimer’s disease. One form of this protein, APOE4, is thought to be the largest genetic risk factor for late-onset Alzheimer’s disease. APOE is also important in regulating lipid metabolism in the brain.
Potential benefits beyond plaque removal
The researchers also found that levels of APOE and its receptors involved in regulating amyloid plaques increased after the enzyme was removed from neurons. These receptors are important for maintaining healthy communication between neurons and supporting lipid metabolism.
Callahan said previous studies have shown that activating related pathways may make Alzheimer’s patients more resistant to cognitive decline, even in the presence of significant plaque buildup.
“This is particularly important from a clinical perspective because patients are typically diagnosed with the disease after large amounts of amyloid plaques have accumulated in the brain. By not only lowering amyloid levels, but also by increasing resilience to these pathological changes, clinical benefit may be maximized,” Callaghan said. “Targeting neuronal IDOL may have multiple therapeutic effects in Alzheimer’s disease by simultaneously reducing amyloid burden while enhancing neuroprotective effects.”
Researchers plan to develop future Alzheimer’s disease drugs
The research team is currently exploring several approaches to developing drugs that target the IDOL enzyme. Future research will focus on testing the safety of potential compounds and assessing how well they perform in preclinical models, Kim said.
The scientists also plan to investigate whether blocking IDOL can maintain synaptic connections between neurons and reduce tau pathology, another key hallmark of Alzheimer’s disease.
