Microtubule modification influences cellular response to amyloid-β exposure

Abstract

During the normal aging process, cytoskeletal changes such as a reduction in density or disruption of cytoskeletal components occur that can affect neuronal function. As aging is the biggest risk factor for Alzheimer's disease (AD), this study sought to determine how microtubule (MT) modification influences cellular response upon exposure to β-amyloid1-42 (Aβ1-42), which is implicated in AD. The MT networks of hypothalamic GT1-7 neurons were modified by common disrupting or stabilizing drugs, and then the physical and mechanical properties of the modified neurons were determined. The MT modified neurons were then exposed to Aβ1-42 and the ability of the neurons to cope with this exposure was determined by a variety of biochemical assays. Flow cytometry studies indicated that MT disruption reduced the binding of Aβ1-42 to the plasma membrane by 45% per cell compared to neurons with stabilized or unaltered MTs. Although the cells with disrupted MTs experienced less peptide-membrane binding, they experienced similar or increased levels of cytotoxicity caused by the Aβ1-42 exposure. In contrast, MT stabilization delayed toxicity caused by Aβ1-42. These results demonstrate that MT modification significantly influences the ability of neurons to cope with toxicity induced by Aβ1-42.

Keywords

• Alzheimer’s disease; β-amyloid; microtubules; cellular mechanics; neurodegeneration; protein aggregation