Kosman Awarded Grant to Study Protein Linked to Alzheimer’s

Kosman seeks to unravel the connection between amyloid precursor protein (APP) and iron and discover how as we age it can become the root in initiating events in the progression of Alzheimer’s.

The project is titled “Ferroportin and APP: Regulation of Iron Trafficking at the Blood-Brain Barrier” and is being funded by the National Institute of Neurological Disorders and Stroke.

Ferroportin is a protein that regulates iron’s transport from the blood into the brain.

The proposal outlines experiments that blend biochemistry, structural biology, cell biology and genetics to understand how APP and iron interact, the consequences of this interaction with respect to iron biology and iron regulation, oxidative stress and blood-brain-barrier integrity.

APP is the source of the amyloid-beta that form the protein masses — the plaques — in the brain that are the specific mark of Alzheimer’s disease.

“Our objective is to find how the parameters are modulated by the Alzheimer’s protein APP,” says Kosman, the principal investigator on the grant. “The question has always been: Does iron cause these plaques or do these plaques just accumulate iron? What’s the role of iron in plaque formation and thus the progression of Alzheimer’s disease?”

While there have been numerous papers correlating APP with Alzheimer’s disease, there has been little published research about its physiologic function.

“Our premise is that one of its important functions is to regulate the flux of iron across the blood-brain barrier and in and out of what we call the neuro-vascular unit,” Kosman says.

Kosman believes the research can add greatly to the understanding of Alzheimer’s.

“The implications from this hypothesis are profound, both from a fundamental understanding of a new mechanism that regulates iron metabolism and from the perspective that APP, while inextricably linked to Alzheimer’s disease, has an as-yet unknown function,” Kosman says. “If we really see this picture of the physiology, then we’re smarter in how we’re going to address this long-term neurodegenerative disease, which is obviously going to be more and more of a problem as the population becomes more and more aged.”

Kosman and others have demonstrated that APP serves a critical role in making sure the brain gets the right amount of iron, an essential trace mineral.

“It’s important to understand how iron trafficking in the brain is regulated, because iron is toxic. It’s also very essential. So there’s this balance, particularly in neurons, which are the most energy consuming cells in your body,” Kosman says.

That balance is crucial.

“Iron is critical to brain function and serves as the catalyst that satisfies the brain’s appetite for energy,” Kosman says. “However, iron is also associated with the amyloid-beta plaques in the brain that are the specific mark of Alzheimer’s, suggesting that as we age, the APP-iron connection becomes dysregulated, turning an essential function into a pathologic one.”

Two of Kosman’s previous doctoral students — Ryan McCarthy, PhD, now a postdoctoral research associate at the Harvard T.H. Chan School of Public Health, and Changyi Ji, PhD, a postdoctoral associate at the University of Rochester’s school of medicine — were involved in starting the research work.

It has been continued by Adrienne Dlouhy, PhD — who joined the lab following her doctoral work at the University of South Carolina and recently became a scientific workforce specialist at UB’s Clinical and Translational Science Institute — and doctoral candidates Brittany Steimle and Danielle Bailey.

Changliang He, PhD, from Sichuan Agricultural University in China, worked extensively on the regulation of APP processing work during a six-month visit, work that is continuing under the direction of Bailey.