CAREER: The Role of Mechanical Properties in Amyloid Binding to Cellular Surfaces

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The research objective of this award is to gain an understanding of how age-related mechanicalchanges in cells increase their susceptibility to being bound by the amyloid peptide andits aggregate forms. A hallmark of Alzheimer's disease (AB) is the rearrangement of the Ab to anon-native conformation that promotes the formation of toxic, nanoscale aggregates. Thelargest risk factor for AD is aging, and the proposed work aims to determine how mechanicalchanges in cells associated with aging increases the ability of AB to bind cellular surfaces. Forthese studies, age-related alterations of membranes will be mimicked by specific chemical andcompositional alterations to lipid bilayers, which are models of a cells plasma membrane, priorto exposure to AB. In parallel, the ability of AB to bind to cells in culture, with chemically inducedchanges in mechanical properties designed to mimic ageing, will also be determined. Agerelatedchanges include oxidative damage, enhanced cholesterol content of the membrane, anddisruption of cytoskeletal components. Scanning probe microscopy techniques will be applied tocorrelate mechanical changes, measured with nanoscale spatial resolution, of the model lipidbilayers and cells with their susceptibility to Ab binding and subsequent disruption.If successful, the proposed research would yield detailed understanding of how cellular surfaceproperties associated with aging influence AB membrane binding, aggregation, and ultimatelytoxicity. The binding of Ab and its aggregate forms to cellular surfaces represents a fundamentalstep in potential toxic mechanisms associated with AD and has broader implications inprotein/membrane interactions. The educational plan focuses on providing meaningful researchexperience to pre-service science, technology, engineering, and mathematics (STEM) teachers,with a particular focus on pre-service teachers (PSTs) planning on careers in the region ofAppalachia, as persons from economically-distressed counties in this region areunderrepresented in STEM fields. The PSTs will develop a lesson or teachable unit based ontheir research activities that can be directly translated into the classroom. It is believed thatparticipating PSTs will be able to improving science education in the region