Alzheimer's disease, the most common age-related dementia, is characterized by increased oxidative damage, neurofibrillary tangles composed principally of altered tau, and plaques containing Abeta aggregates and dystrophic neurons. This proposal will test the hypothesis that neuronal oxidative damage initiated by Abeta peptides leads to the generation of reactive products of lipid peroxidation that modify neuronal tubulin leading to collapse of neuronal nicrotubules and disassociation of tau. This hypothesis will be tested by completing four specific aims that will determine the structural and functional alterations in neuronal tubulin and release of tau caused by direct application of reactive lipid peroxidation products, by Abeta peptide-mediated activation of glial innate immune response, and by increased intraneuronal accumulation of Abeta peptides in cell culture. Lastly, this project will determine the level of corresponding functional alterations in tubulin in diseased regions of brain from patients with AD compared to non-licensed regions and corresponding regions from age-matched controls. The key methods will include a tubulin polymerization assay, centrifugation -induced fractionation of microtubule-associated tau and tubulin from free cytosolic tau and tubulin, and elucidation of modified amino acids by immunoassays. Characterization of modified tubulin by oxidative damage will delineate a molecular mechanism by which the major pathogenic features of AD may be connected and may lead to further investigation of protein and antioxidant-targeted therapies for AD.
| Boutte, Angela M; Woltjer, Randall L; Zimmerman, Lisa J et al. (2006) Selectively increased oxidative modifications mapped to detergent-insoluble forms of Abeta and beta-III tubulin in Alzheimer's disease. FASEB J 20:1473-83 |
| Boutte, Angela M; Neely, M Diana; Bird, Thomas D et al. (2005) Diminished taxol/GTP-stimulated tubulin polymerization in diseased region of brain from patients with late-onset or inherited Alzheimer's disease or frontotemporal dementia with parkinsonism linked to chromosome-17 but not individuals with mild cognitive J Alzheimers Dis 8:1-6 |
