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Chemists Garner New Insights into Protein Linked to Alzheimer’s Disease

Chemists Garner New Insights into Protein Linked to Alzheimer’s Disease

Alzheimer's disease, the sixth leading cause of death in the United States, has proven especially thorny for researchers: no cure has been found, nor has there been any treatment proven to slow the progression of the disease once it sets in. In a new study published in the Proceedings of the National Academy of Sciences, scientists have taken a back-to-the-beginning approach, examining what happens at the start of a chain reaction that occurs before onset of the disease.

Amyloid plaques in a brain tissue sample. Credit: CDC/ Teresa Hammett.

Dave Thirumalai, a theoretical chemist at The University of Texas at Austin and chair of the Department of Chemistry, and John Straub, a computational chemist at Boston University, teamed up to understand how a mutation in a normal protein can create amyloid β, a key contributor to Alzheimer's disease. Amyloid β builds up as a plaque in the brains of people with the disease, apparently leading to dementia and other symptoms.

Amyloid β occurs when a protein found in healthy brains – called the amyloid precursor protein – gets cut by an enzyme in a particular way. Thirumalai and the other researchers wanted to understand what interactions were occurring in the membrane, and under which circumstances, to cause the precursor to be severed in such a way that it mutates into amyloid β.

"Several enzymes cut this amyloid precursor protein, which is a very long protein spanning the membrane and outside the membrane," Thirumalai said. "Some products of cutting it are benign, some are not. One can lead to Alzheimer's disease."

The scientific team has spent several years examining how circumstances in the membrane can trigger the disease-causing mutation in the precursor protein. In the latest study, Thirumalai and colleagues report that variations in the membrane, as well as in the structure of the protein, can interact in ways that lead to production of amyloid β. Drug developers could potentially use insights from such studies to understand a new way to prevent the onset of the disease.

Thirumalai and the other scientists plan to continue this line of exploration, including looking into how cholesterol affects the interactions between the membrane, the precursor protein, and the enzyme each time the disease-causing mutation occurs.

"In order to devise a therapy against this process, you need to understand the life cycle of the amyloid precursor protein and figure out what it is doing and what the membrane is doing," Thirumalai says. "These promising leads and new research that we and many others are exploring will hopefully in the end give us a better target for therapy. I'm cautiously optimistic about that."

The group's research was funded with a grant from the National Institutes of Health. 

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Saturday, 04 February 2023

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