AEP Inhibitors & Alzheimer's

Taking on the Challenge of Neurodegenerative Diseases

Alzheimer's disease is a grim and extensive neurodegenerative disorder that is one of the leading causes of death in older people. It was discovered around 110 years ago by Dr. Alois Alzheimer, who examined the brain of a woman who had died of what was then an unknown mental disorder. He found tangled neural fibers and abnormal clumps outside of the cells, evidence of what is still today seen as the two main mechanisms of the disease. In her brain were neurofibrillary tangles, also called tau tangles, in the neurons, and amyloid beta plaques clumped outside of cells in the nervous system. These two mechanisms, and the connections between them, are central to Keqiang Ye's groundbreaking research at Emory.

Ye is a professor and neuroscientist at Emory that specializes in experimental pathology. He began his experience at Emory in a PhD program, where he accidentally created an anti-cancer drug. That was the beginning of Ye's work and calling in drug development. Since then, he has focused his efforts on Alzheimer's disease and leads innovative research into potential medicines. "I was trained as an organic chemist, I've always had an interest in creating medicine," Ye says, "a drive to push my discoveries into a product that society can benefit from." Ye's research is a cutting-edge product of his ambition, on the path to revolutionize Alzheimer's' treatments.

Keqiang Ye, PhD

In explaining his work, Ye begins with Hegelian philosophy. Hegelianism argues that there is one driving force behind any process that dominates and governs all other forces. In the field of medicine, this is the theory that there is one key mechanism above all others in contributing to any given disease. This is what Ye found in the enzyme asparagine endopeptidase, or AEP.

Ye knew that this enzyme only mobilized in acidic environments in the body, and that certain functions in the brain, like pH levels, are regulated by oxygen concentration. As we age, fatty acids are deposited in our arteries, decreasing the blood flow and oxygen supply to the brain. This brings the pH to acidic levels where this enzyme then activates and becomes a key mechanism in forming both the neurofibrillary tangles and amyloid beta plaques that are so destructive to the brain, acting as what Hegelian thought would categorize as the dominant force and essential link within these two processes.

In a normally functioning body, AEPs are in various locations, playing an important role in chopping up proteins. In Alzheimer's and other neurodegenerative disorders, AEP's are seen going rogue. They begin to destroy proteins unnecessarily, attacking those responsible for vital cell processes and modifying them in a way that plays an important role in creating Alzheimer's destructive neural formations. This is a striking medical discovery. Sean Kim, managing licensing associate in The Office of Technology Transfer, stands by the opinion that "inhibiting AEP with small molecule drug candidates has high potential to impact the development of both amyloid precursor protein and tau, the two major pathogenic players in Alzheimer's disease and other neurodegenerative diseases, and ultimately may prove to be an effective therapeutic for these diseases."

Human Brain

After identifying the AEP enzyme as an overarching culprit, not only to processes integral to Alzheimer's disease but also to Parkinson's and certain cancers, Ye's next step was to find out how to stop it. Ye's team produced a drug that binds to AEPs and prevents them from attacking beneficial proteins. While current treatments on the market can only partially alleviate symptoms, AEP inhibitors prevent the development of tau tangles and amyloid beta plaques and may-actually stop or slow down the progression of these diseases.

Neurodegenerative diseases are difficult to treat because many drugs have trouble crossing the blood-brain barrier, a protective set of properties in the brain's capillaries that regulate what gets to the brain through the central nervous system. The barrier filters out toxins and pathogens, but also many beneficial molecules found in potential drugs. Strategically, Ye's AEP inhibitors are composed of smaller molecules that are more likely to be able to pass through to the brain. His drug candidates have also shown promise for the potential treatment with low cytotoxicity, meaning it won't have adverse effects those taking it.

Targeting this enzyme, existing at the root of the two main processes in Alzheimer's disease, is a multifaceted solution. Ye provides a metaphor: "A house is leaking during a rainy day, you can plug one hole but there are many others. What this house needs is a new roof." Ye hopes this drug will eventually provide this kind of overarching protection from one of the most widely afflicting detriments to the aging population.

This innovative idea comes at a time when baby boomers are reaching old age. This will usher in a new mass of diagnoses larger than ever before. Alzheimer's Disease International states that 131.5 million people will have dementia by 2050, almost triple current standings. Ye plans, to take this challenge head on, saying "Let's see how far we can go."

Tech IDs: 15035, 16030, 17217