Q&A: Researcher discusses quest to halt neurodegenerative disorders such as Alzheimer’s disease

Misplaced car keys, forgotten names and other lapses in memory are a normal part of life, especially as you age. However, more serious memory problems can be a sign of cognitive impairment or dementia like Alzheimer’s disease.

Alzheimer’s is a form of neurodegenerative disease where nerve cells are damaged and eventually die. An estimated 7.2 million Americans—or one in nine people over the age of 65—have Alzheimer’s disease, according to the Alzheimer’s Association.

For Scott Selleck, professor of biochemistry and molecular biology at Penn State, these numbers aren’t just staggering. They’re personal. The genetic predisposition for developing Alzheimer’s, known as the APOE gene, runs in his family. Different variants of the APOE gene confer an increased risk of age-related Alzheimer’s, up to 15-fold if you carry the “bad” version of the gene from both parents. Selleck’s mother died of Lewy body dementia, the second most common form of neurodegenerative disease after Alzheimer’s.

In 2017, Selleck stepped down from his role as department head for biochemistry and molecular biology. He wanted to dedicate the rest of his career to understanding how neurodegenerative conditions like Alzheimer’s, Parkinson’s disease and amyotrophic lateral sclerosis (ALS) progress and how to potentially stop them.

“Economists can give you the financial costs to our society of these disorders, but the costs go way beyond that. They’re the grandkid never being able to play a game with their grandparent. The spouse having to take care of their wife or husband when their loved one doesn’t remember their name anymore,” Selleck said. “These costs are going to go up because as our society ages, as the average life expectancy goes up, more people are going to have this diagnosis. So, not to invest in studying these diseases is criminal.”

June is Alzheimer’s and Brain Awareness Month, and in this Q&A, Selleck talks about how he’s working to stop the progression of neurodegenerative diseases like Alzheimer’s.

What is Alzheimer’s disease?

Alzheimer’s may start with subtle changes in memory that are often mistaken as normal lapses in memory, but as time goes on, it becomes clear that these are not normal memory lapses. The rate of loss varies and it’s not the same for every person. There are also differences in how it’s expressed. Some people may primarily have memory loss, while others may also have personality changes, or loss of current memory, but some retention of long-past events.

It’s not a trivial diagnosis. The condition is progressive and gradual, getting worse over time. And the outcome of this degenerative process is death.

What does your research focus on?

Currently, there is no cure for neurodegenerative disorders, and the medications that are available largely target symptoms in the later stages of the disease. We want not just to make things better towards the end of the disease, but to prevent the disease from ever taking hold in the first place.

The best way to push back on a disease is to identify the changes that occur early on and that are linked to disease progression. We are trying to identify those early events and then to devise interventions that could potentially reverse the changes that lead to problems, that lead to decline and neurodegenerative disorders.

What have you found?

To be a healthy cell, you need to repair damage, and you need to be able to produce energy. These processes are deranged in neurodegenerative disorders and contribute to the progression of the disease. They occur long before a clinician can see overt signs in the brain. We’ve identified a signaling pathway that regulates repair, and we can adjust it to push these derangements back toward normal.

Somewhat by happenstance and good luck, a graduate student in my lab made some astute observations that were surprising. A class of cell surface molecules called heparan sulfate-modified proteins serve as co-receptors for many growth factors, meaning that they help amplify the signal from the growth factors. However, they also put the brakes on cell repair.

One important element of cell repair is called autophagy, which means “self-eating” in Latin. That process is compromised in all the major neurodegenerative disorders. When autophagy isn’t working properly, it means cells can’t get rid of damaged mitochondria, which then fail to produce the energy needed. They also generate toxic by-products, known as reactive oxygen species. A failure to remove damaged mitochondria is a major cause in the development of neurodegenerative disease.

It turns out that cell repair pathways are also involved in mobilizing and metabolizing lipids for energy production. Lipids are broken down in mitochondria where they allow for the production of ATP, the energy currency of the cell. If you don’t have healthy mitochondria, you can’t get rid of lipids and lipid accumulation is another hallmark of neurodegenerative disorders.

We found that when we partially inhibited the function of heparan sulfate-modified proteins, this released the brakes on repair systems and prevented the kind of damage that occurs in Alzheimer’s, Parkinson’s disease and ALS. It also improved metabolic pathways that are compromised in neurodegenerative disease.

This research is a work in progress, but it has the potential to reverse the early problems that occur across neurodegenerative disorders. In animal models, we’ve shown that modestly inhibiting this pathway can rescue cells that are otherwise degenerating. The biology we have uncovered is evident across the animal kingdom, including the fruit fly Drosophila, mice and in human cells.

How does research like yours potentially lead to new treatments and medications?

You don’t always know what a particular field of study is going to yield. It may seem unlikely that studying these molecules and developmental systems in animal models, like fruit flies, zebrafish, and mice would lead to something that might serve a role in treating Alzheimer’s, Parkinson’s and ALS. But there is a good possibility it will.

Understanding the mechanisms behind fundamental processes is a key step. Without new knowledge, we wouldn’t be able to find new drugs and treatment options. We have started a drug discovery project targeting the human gene we have identified as a central player in our pathway.

How does working with collaborators in different departments and from different institutions impact your research?

This problem is only going to get solved by collaborative work. People that do medicinal chemistry, physiology, molecular biology, cell biology, behavior—all of these domains have to work together. We cannot silo this. We’ve been able to make as much progress as we have because of colleagues at Penn State, including Melanie McReynolds, assistant professor of biochemistry and molecular biology, and those from the University of Georgia, the University of California, San Francisco and the University of Alabama, who bring their expertise, knowledge and ideas to the table.