Cytoskeletal protein dysfunction and oxidative modification in Alzheimer’s disease
Boutte, Angela Monique
:
2005-12-05
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.