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 impairment.
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.
Boutté
Angela M
AM
Center for Molecular Neuroscience, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.
Neely
M Diana
MD
Bird
Thomas D
TD
Montine
Kathleen S
KS
Montine
Thomas J
TJ
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics* / Q000503:physiopathology; D001921:Brain / Q000187:drug effects* / Q000503:physiopathology; D002886:Chromosomes, Human, Pair 17; D003072:Cognition Disorders / Q000235:genetics* / Q000503:physiopathology; D004252:DNA Mutational Analysis; D003704:Dementia / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D008040:Genetic Linkage; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008869:Microtubule-Associated Proteins / Q000235:genetics; D008870:Microtubules / Q000235:genetics / Q000502:physiology; D017239:Paclitaxel / Q000494:pharmacology*; D020734:Parkinsonian Disorders / Q000235:genetics* / Q000503:physiopathology; D053766:Presenilin-2; D014404:Tubulin / Q000235:genetics* / Q000502:physiology; D050257:Tubulin Modulators / Q000494:pharmacology; D016875:tau Proteins
C054369:MAPT protein, human; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; C508861:PSEN2 protein, human; D053766:Presenilin-2; D014404:Tubulin; D050257:Tubulin Modulators; D016875:tau Proteins; D017239:Paclitaxel