Alzheimer's disease (AD) is a devastating neurodegenerative disease that affects millions of Americans, and presents one of the most pressing and challenging mysteries in biomedical science today. Multiple lines of research are aimed at achieving methods for early diagnosis and treatment as well as a basic understanding of the biology involved. One promising hypothesis regarding the early stages of the disease originates in observations regarding the formation of amyloid beta (A?) plaques, which are a unique pathological hallmark of AD. Recent research indicates that small aggregates of A? that nucleate prior to the formation of plaques may in fact be directly toxic to cells. These relatively small aggregates (oligomers and protofibrils) have been shown to interfere in synaptic signaling, and can produce toxic effects in vivo. In addressing the toxic effect of these oligomers, an interesting connection between Alzheimer's disease and the mammalian prion protein (PrPc) has come to light, providing us with what might be a crucial link in understanding the initial processes leading to progressive dementia and neuronal loss. PrPc is a cell-surface protein with an as-yet unknown function. However, there is now considerable evidence that aggregates of synthetic A? bind specifically to PrPc, producing downstream effects including synaptic alteration and cell death. This connection opens up a new area of research, one with the potential to impact our understanding of AD, leading to improved methods for following and targeting the early stages of the disease. A crucial linkage that adds interest to this mechanism lies in the fact that PrPc itself, in a misfolded state (denoted PrPSc), acts as the infectious aget in transmissible spongiform encephalopathies (TSEs), spreading through the brain and producing progressive dementia and neurodegeneration. This raises questions about whether PrPc acts to promote neurodegenerative changes in cells in the early stages of both AD and TSEs through interactions with toxic aggregates. The project put forth in this proposal aims to describe the interaction between PrPc and toxic forms of A? using specific biophysical methods for isolating the protein and the peptide aggregates together as a single unit, and then characterizing the size and conformation of the A? aggregates. Our hope is that this will lead to a better understanding of which A? aggregates present the greatest threat to neuronal health, and which aggregates might serve as markers for early diagnosis or provide targets for treatment. Additionally, we seek to shed light on the mechanism of toxicity for PrPSc using a novel approach designed to capture and characterize early binding events. Because the detailed toxic interactions between PrPSc and neurons have not yet been characterized, this approach holds potential for opening a new field of drug targeting and preventative treatment for TSEs.

Public Health Relevance

One of the biggest challenges to our understanding of progressive neurodegenerative diseases like Alzheimer's Disease (AD) lies in finding a means of diagnosing and treating the disease early in its progress, before the more devastating neurodegenerative effects take hold. Soluble oligomers of the amyloid beta peptide (A) engage in toxic interactions with cellular prion proteins (PrPc) on the surface of neurons;this interaction may be the mechanism leading to early changes in cognitive function. Our data upholds previously shown strong binding interactions between PrPc and A, which we propose to use in order to isolate and, for the first time, fully characterize the toxic A oligomers thoght to promote the progression of AD.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZRG1)
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Wong, May
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Boston University
Schools of Medicine
United States
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Bove-Fenderson, Erin; Urano, Ryo; Straub, John E et al. (2017) Cellular prion protein targets amyloid-? fibril ends via its C-terminal domain to prevent elongation. J Biol Chem 292:16858-16871