Investigating the Relationship between Cellular Mechanics and Beta Amyloid in Alzheimer's Disease

Abstract

Listen

Translate article

The beta amyloid (Aβ) peptide was first implicated in the formation of amyloid plaques, a characteristic of Alzheimer's disease (AD), nearly 30 years ago. Misfolding of the Aβ peptide into nonnative conformations promotes the formation of aggregates such as oligomers, annular aggregates and fibrils that can impair cellular function. Although these aggregates are known to be toxic, the exact mechanism of their cytotoxicity remains unclear. As aging is associated with AD, we explored how cytoskeletal degradation, associated with the aging process, modulates a cell's ability to cope with exposure to exogenous Aβ. In this study, hypothalamic neurons, of the GT1-7 cell line, were treated using a variety of cytoskeletal altering drugs. The mechanics of the altered neurons were examined by atomic force microscopy-based techniques (force-distance curve and force volume analysis) and the altered neurons were then exposed to the Aβ peptide to determine how the cytoskeletal network affects peptide binding and toxicity. Binding studies were performed using fluorescence activated cell sorting and toxicity was examined using a variety of biochemical assays. Finally, the topography and mechanics of the the aged neurons exposed to Aβ were examined to determine the impact of Aβ binding. This research gives a mechanistic understanding of AD pathology in relation to the cytoskeleton and examines the potential for cytoskeletal stabilization as a therapeutic intervention for combating AD.