Abstract
Neuronal microtubules are morphologically abnormal in diseased regions of brain from patients with late-onset Alzheimer's disease (LOAD). Here we tested the hypothesis that tubulin derived from gray matter of patients with multiple forms of dementia was functionally impaired. Following taxol/GTP stimulation of tubulin polymerization of gray matter extracts we observed reduced capacity of tubulin to polymerize in LOAD, but not individuals with mild cognitive impairment (MCI), compared to controls. Moreover, we observed similarly reduced taxol/GTP-stimulated tubulin polymerization from gray matter obtained from patients with AD caused by PSEN2 N141I mutation or frontotemporal dementia with parkinsonism linked to chromosome-17 caused (FTDP-17) by TAU V337M or P301L mutation. Our results show that modification of tubulin function may contribute to intermediate or late stages in the pathogenesis of sporadic and inherited AD as well as FTDP-17.
Publication types
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Comparative Study
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Aged
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Aged, 80 and over
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Alzheimer Disease / genetics*
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Alzheimer Disease / physiopathology
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Brain / drug effects*
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Brain / physiopathology
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Chromosomes, Human, Pair 17*
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Cognition Disorders / genetics*
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Cognition Disorders / physiopathology
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DNA Mutational Analysis
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Dementia / genetics*
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Dementia / physiopathology
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Female
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Genetic Linkage
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Humans
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Male
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Membrane Proteins / genetics
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Microtubule-Associated Proteins / genetics
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Microtubules / genetics
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Microtubules / physiology
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Paclitaxel / pharmacology*
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Parkinsonian Disorders / genetics*
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Parkinsonian Disorders / physiopathology
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Presenilin-2
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Tubulin / genetics*
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Tubulin / physiology
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Tubulin Modulators / pharmacology
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tau Proteins
Substances
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MAPT protein, human
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Membrane Proteins
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Microtubule-Associated Proteins
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PSEN2 protein, human
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Presenilin-2
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Tubulin
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Tubulin Modulators
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tau Proteins
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Paclitaxel