Unknown Alzheimer’s trigger identified – scientists look to block it

Researchers at the Indiana University School of Medicine have found a way to equip the brain to fight back against Alzheimer’s disease. Scientists at the school have uncovered a likely new approach to tackling Alzheimer’s disease through focusing on an enzyme in the brain called IDOL. In the study conducted, taking out the enzyme from neurons already in the brain resulted in profoundly lowered amyloid plaques. This, they say, is a crucial win on the journey to besting the disease, as amyloid plagues are a key biological indicator of Alzheimer’s. From not only slowing down the progression of the disease, researchers say this discovery highlights an opportunity to support the brain to more effectively work against damage linked to the disease.

Building on progress

Building upon past verified research, researchers have started to zero in on amyloid plaque as an avenue for Alzheimer’s break-through. Recent research, and commercial impact, has been highlighted through the U.S Food and Drug Administration approving two disease altering drugs, lecanemab and donanemab, which within their core mechanics function through clearing the plaque accrual in the brain. Both drugs have been identified as treatment options to plateau the disease’s progression, stabilising patients through impeding the rate of deterioration.

Further than slowing down however, the Indiana University team sees targeting the IDOL enzyme as opening up an alternative potential approach in tackling Alzheimer’s, in conjunction with already beneficial processes, such as enhancing relationships between supportive healthy lipid metabolism and brain cells. In a nutshell, many see this as a move from reactionary defensive to proactive actioning.

Jungsu Kim, the P. Michael Conneally Professor of Medical and Molecular Genetics at the school shares, “what makes this exciting is that we now have a specific target that could lead to a new type of treatment”.

“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.”

Findings

Published in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, the findings come about after the team’s novel approach in testing theories at the frontier of this science.

Researchers constructed two separate animal models of the disease through removing the IDOL gene in separate brain cell types, namely neurons and microglia. Cell types that are immune cells within the brain.

The team expected the bigger player to be microglia, in its prowess to remove amyloid plaques. Functionally these immune cells are already hard at work clearing damaging material from the brain and are in themselves the main manufacturers of IDOL.

And yet it was the removal of IDOL from neurons that had the most prolific impact.

Hande Karahan, PhD is an assistant research professor of medical molecular genetics. He shares that removing IDOL from neurons was found to lower plaque levels, yes, but in addition, it lowered levels of apolipoprotein E (APOE), a protein also closely linked with Alzheimer’s disease.

In previous research, a form of this protein, APOE4, has been found to mark the clearest indicator of genetic risk when it comes to late onset Alzheimer’s. The process of removing IDOL from the neuron, resulting in impacting APOE levels, has lead to significant potential for breakthroughs the team believes.

Further benefits

In understanding and meeting the challenge of treating Alzheimer’s, researchers argue the mounting cumulative benefits from findings are contributing to being on the proactive front foot, in making resistance to decline, not just slowing the rate of deterioration, a possibility.

In another aspect of the study, the team found higher levels of receptors, whose function is in regulating APOE and amyloid plaques, after the enzyme was deleted from neurons. These critical receptors already serve an integral process in keeping brains healthy, through sustaining and protecting healthy communication of neurons and supportive lipid metabolism. The research now uncovers that the approach in removing the IDOL protein from neurons yields higher rates of these already fundamentally important actors in the brain, as well as potentially playing a game-changing part in fighting Alzheimer’s.

Karahan notes that prior research has established that activating a pathway of communication between neurons and lipid metabolism may have a powerful impact on people with the disease reliably resisting cognitive deterioration. This the case even in the face of substantial plaque buildup detected. Their current research highlights a potential new tool to exponentially increase the numbers of receptors working for good.

Karahan shares, “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.”

“Targeting neuronal IDOL may offer multiple therapeutic benefits in Alzheimer’s disease by simultaneously reducing amyloid burden while enhancing neuroprotective effects.”

Work continues

The team now looks to consider opportunities to further their research. The group is set to pursue developing optimal iterations of drug formulation to target the IDOL enzyme.

Kim has noted that oncoming studies will target understanding, and testing further, the safety of compounds that have shown promise but as yet have not been verified through clinical study. He shares that their research group is looking to evaluate the efficacy of the findings in the precise and invaluable standard of preclinical models.

The team additionally is set to explore whether fully limiting IDOL can lead to the preservation of synaptic connections between neurons found in human brains, and in so doing, drastically lower tau pathology, a key element of Alzheimer’s disease.