Cytoskeletal protein dysfunction and oxidative modification in Alzheimer’s disease

Abstract

Our aged population is poised to expand dramatically within the next decade. In Alzheimer’s disease (AD) pathogenesis studies, the end point hallmarks or lesions are known and well studied; however, the exact processes leading to these lesions are not. Defining early pathological events at the molecular and protein level and targeting appropriate therapies to pre-clinical or early stage dementia is necessary to avert the coming public health crisis. This project showed that lipid peroxidation products can lead to microtubule dysfunction that is characteristic of AD and that this is associated with their accumulation on tau from among the cytoskeletal proteins investigated. In contrast, another type of protein oxidation was observed selectively on Beta-III tubulin using mass spectrometry. Together, these data indicate that multiple oxidative modifications to cytoskeletal proteins are likely occurring in AD and that these can contribute to cytoskeletal dysfunction, leading to a modified model of AD pathogenesis. Furthermore, the results suggest that approaches to limit protein oxidation may have the downstream effect of suppressing protein insolubility and its consequences. Perhaps, with further investigation, studies will be able to define drug-treatable targets to prevent and slow neurodegenerative disease progression.