Cognitive decline in Alzheimer?s Disease (AD) and many other age-related dementias have long been associated with the presence of insoluble amyloid plaques that disrupt normal synaptic functioning. However, more recent studies have revealed that synapse impairment from AD is much more potently associated with soluble amyloid-beta oligomers (abo), rather than from insoluble fibrils. Soluble oligomers are structurally irregular and promiscuously bind to membrane proteins, thereby dysregulating downstream amyloid assemblies such as tau. These properties, unfortunately, have also made it difficult to experimentally characterize abo, since oligomeric states can be transient or otherwise observed as noise. Multiple genome-wide screening methods have identified cellular prion protein (PrPc) as a putative target of abo, and subsequent studies have confirmed a pathophysiological pathway in AD involving abo-PrPc binding. Interestingly, ab monomers and insoluble fibrils do not bind to PrPc, thus the binding domain of PrPc can be exploited in peptide aptamers to target and stabilize abo. Here, we seek to utilize these interactions by designing biomimetic PrPc peptides that complex soluble abo. Molecular simulations and amyloid-characterizing experiments will be combined to optimize aptamer-abo interactions in order to abrogate binding of abo to PrPc. While aptamers are unlikely to serve as an AD therapeutic, amyloid-targeting PrPc peptides can guide the construction of next-generation agents that cross the blood-brain barrier and potently inhibit the toxicity of abo. Similarly, identification of abo by aptamers can potentially enable the tracking of soluble oligomers through fluorescent tagging during the formation of insoluble fibrils. Given that there are few, if any methodologies to target abo, this proposal would seek to isolate soluble oligomers and identify the limitations of their interactions with membrane proteins. In order to synergistically combine molecular dynamics simulations with experiments, mentoring will be carried out on the use of NMR spectroscopy, chromatography, and ligand-binding assays to measure oligomer structure, size, and the ability to bind PrP proteins, respectively. Mentoring will include regular meetings, coursework, workshops, and immersion in the laboratory of the primary mentor. Additionally, this study will seek to bridge basic biophysical research with clinically-relevant systems through the translation of model aptamers from simulations into experiments. Results will be connected to and interpreted in the context of Alzheimer?s Disease. The protocols and products developed as a result of this study will subsequently inform follow-up studies of soluble amyloid toxicity in live cells, with extensions to multiple neurodegenerative diseases.

Public Health Relevance

While Alzheimer?s Disease (AD) and other age-related dementias are correlated with a buildup of large protein plaques in otherwise-healthy neurons, disease severity appears to be linked to the presence of small, irregular plaques that amplify signals of dysregulation. On their own, experiments have been unable to characterize irregular plaque signaling, therefore the goal of this proposal is to combine molecular simulations with experiments in order to stabilize and neutralize promiscuous plaques with pieces of the proteins they bind to. Successfully blocking promiscuous plaque signaling in model systems will provide the necessary requirements for potential AD therapeutics that seek to mitigate neurodegeneration, rather than abolishing it entirely.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Scientist Development Award - Research & Training (K01)
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Neuroscience of Aging Review Committee (NIA)
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Mackiewicz, Miroslaw
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Yale University
Schools of Medicine
New Haven
United States
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