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

West Virginia University Research Corporation, Morgantown WV

Investigators

Abstract

The research objective of this award is to gain an understanding of how age-related mechanical changes in cells increase their susceptibility to being bound by the amyloid peptide and its aggregate forms. A hallmark of Alzheimer's disease (AB) is the rearrangement of the Ab to a non-native conformation that promotes the formation of toxic, nanoscale aggregates. The largest risk factor for AD is aging, and the proposed work aims to determine how mechanical changes in cells associated with aging increases the ability of AB to bind cellular surfaces. For these studies, age-related alterations of membranes will be mimicked by specific chemical and compositional alterations to lipid bilayers, which are models of a cells plasma membrane, prior to exposure to AB. In parallel, the ability of AB to bind to cells in culture, with chemically induced changes in mechanical properties designed to mimic ageing, will also be determined. Agerelated changes include oxidative damage, enhanced cholesterol content of the membrane, and disruption of cytoskeletal components. Scanning probe microscopy techniques will be applied to correlate mechanical changes, measured with nanoscale spatial resolution, of the model lipid bilayers and cells with their susceptibility to Ab binding and subsequent disruption. If successful, the proposed research would yield detailed understanding of how cellular surface properties associated with aging influence AB membrane binding, aggregation, and ultimately toxicity. The binding of Ab and its aggregate forms to cellular surfaces represents a fundamental step in potential toxic mechanisms associated with AD and has broader implications in protein/membrane interactions. The educational plan focuses on providing meaningful research experience 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 of Appalachia, as persons from economically-distressed counties in this region are underrepresented in STEM fields. The PSTs will develop a lesson or teachable unit based on their research activities that can be directly translated into the classroom. It is believed that participating PSTs will be able to improving science education in the region