School of Medicine

Study details molecular roots of Alzheimer’s

A new study at Washington University School of Medicine in St. Louis details the structure of TREM2, a protein involved in Alzheimer's disease and other neurodegenerative disorders. Researchers found that mutations associated with Alzheimer's alter the surface of the protein, while mutations linked to another brain disorder disrupt the protein's interior. Such alterations may impair TREM2's normal role in cleaning up cellular waste via a process called phagocytosis. (Image: Daniel L. Kober)

Scientists at Washington University School of Medicine in St. Louis have detailed the structure of a molecule that has been implicated in Alzheimer’s disease. Knowing the shape of the molecule — and how that shape may be disrupted by certain genetic mutations — can help in understanding how Alzheimer’s and other neurodegenerative diseases develop and how to prevent and treat them.

The study is published Dec. 20 in the journal eLife.

The idea that the molecule TREM2 is involved in cognitive decline — the hallmark of neurodegenerative diseases, including Alzheimer’s — has gained considerable support in recent years. Past studies have demonstrated that certain mutations that alter the structure of TREM2 are associated with an increased risk of developing late-onset Alzheimer’s, frontal temporal dementia, Parkinson’s disease and sporadic amyotrophic lateral sclerosis (ALS). Other TREM2 mutations are linked to Nasu-Hakola disease, a rare inherited condition that causes progressive dementia and death in most patients by age 50.

“We don’t know exactly what dysfunctional TREM2 does to contribute to neurodegeneration, but we know inflammation is the common thread in all these conditions,” said senior author Thomas J. Brett, PhD, an assistant professor of medicine. “Our study looked at these mutations in TREM2 and asked what they do to the structure of the protein itself, and how that might impact its function. If we can understand that, we can begin to look for ways to correct it.”

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