Alzheimer's Disease Research Today is a free monthly online journal that collates and summarizes the latest research about Alzheimer's Disease, including details on diagnosis, memory loss, heredity, treatment, medication.

Selectively increased oxidative modifications mapped to detergent-insoluble forms of Abeta and beta-III tubulin in Alzheimer's disease.

Boutte AM, Woltjer RL, Zimmerman LJ, Stamer SL, Montine KS, Manno MV, Cimino PJ, Liebler DC, Montine TJ

Center for Molecular Neuroscience, Vanderbilt University, Nashville, Tennessee, USA.

Deleterious post-translational modifications (PTMs) to the neuronal cytoskeleton are a proposed mechanistic link between accumulation of amyloid (A) beta peptides and subsequent abnormalities of tau and neurodegeneration in Alzheimer's disease (AD). Here we tested the hypothesis that PTMs on neuronal tubulins selectively accumulate in a pathological protein fraction in AD. We used new software, P-MOD, to identify comprehensively and map PTMs using mass spectral data from soluble (normal) and detergent-insoluble (pathological) protein fractions from AD, as well as total extracts from controls, for selected proteins: Abeta, tau, apolipoprotein (apo) E, glial fibrillary acidic protein (GFAP), alpha-III tubulin, and beta-III tubulin. Our results confirmed direct observations of others by identifying methionine (M) sulfoxides at Abeta position 35 and numerous sites of tau phosphorylation in detergent-insoluble protein from AD, while no PTMs were enriched on primarily astrocyte-derived apoE or GFAP in this fraction. P-MOD mapped several abundant M sulfoxides to neuron-enriched beta-III tubulin but not its heterodimeric partner, neuron-enriched alpha-III tubulin, a result confirmed by selective suppression of CNBr-mediated cleavage of beta-III tubulin. These findings are the first comprehensive assessment of PTMs in AD and point to oxidative modification of beta-III tubulin as a potential contributor to the neuronal cytoskeletal disruption that is characteristic of AD.

Published 3 July 2006 in FASEB J, 20(9): 1473-83.
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