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2016 Grants - Meredith
Brain Amyloid Seeded Oligomers
Stephen Meredith, M.D., Ph.D.
University of Chicago
2016 Zenith Fellows Award
What triggers the accumulation and spread of beta-amyloid in the brain during Alzheimer’s disease?
Beta-amyloid is a protein fragment at the focus of research into the causes of Alzheimer’s disease. It is normally found in the brain but during the disease process, it forms small clumps known as oligomers, which are thought to be toxic to nerve cells. Eventually, beta-amyloid oligomers combine to form even larger structures known as fibrils, which then form amyloid plaques in the brain, one of the characteristic features of Alzheimer’s disease.
Stephen Meredith, M.D., Ph.D., and colleagues have been studying the detailed molecular structure of beta-amyloid fibrils and working to identify what may trigger their development in Alzheimer’s disease. They have found that fibrils can have different structures from one person to the next, but that the fibrils found in different parts of the brain of a single person are generally the same. The researchers hypothesize that formation of an initial oligomer or fibril in one area of the brain may trigger the accumulation of other oligomers and subsequent plaque development in different areas of the brain. This process is called “seeding” and could contribute to the “spreading” of beta-amyloid accumulation in the brain.
Dr. Meredith and colleagues have proposed a series of detailed studies focused on the structure and formation of beta-amyloid fibrils and oligomers. They plan to obtain samples of beta-amyloid fragments from the brains of people who had Alzheimer’s disease and use it to seed the formation of oligomers in the laboratory. The researchers will then use sophisticated techniques, such as nuclear magnetic resonance, to study the structure of these oligomers in detail. Dr. Meredith’s team will study how different types of beta-amyloid oligomers and fibrils may influence the formation of amyloid plaques.
These studies will help scientists understand what triggers the formation of beta-amyloid oligomers, fibrils, and plaques in the brain. Knowledge of different oligomer and fibril structures is important because they could have varying levels of toxicity and may respond differently to treatments. Understanding these issues could help scientists develop novels ways to prevent, slow or halt disease progression.