학술논문
Hyperdynamic Microtubules, Cognitive Deficits, and Pathology Are Improved in Tau Transgenic Mice with Low Doses of the Microtubule-Stabilizing Agent BMS-241027.
Document Type
Article
Author
Barten, Donna M.; Fanara, Patrizia; Andorfer, Cathy; Hoque, Nina; Wong, P. Y. Anne; Husted, Kristofor H.; Cadelina, Gregory W.; DeCarr, Lynn B.; Ling Yang; Victoria Liu; Fessler, Chancy; Protassio, Joan; Riff, Timothy; Turner, Holly; Janus, Christopher G.; Sankaranarayanan, Sethu; Polson, Craig; Meredith, Jere E.; Gray, Gemma; Hanna, Amanda
Source
Subject
*TRANSGENIC mice
*MICROTUBULES
*PATHOLOGY
*TAU proteins
*ALZHEIMER'S disease
*ANIMAL models in research
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Language
ISSN
0270-6474
Abstract
Tau is a microtubule (MT)-stabilizing protein that is altered in Alzheimer's disease (AD) and other tauopathies. It is hypothesized that the hyperphosphorylated, conformationally altered, and multimeric forms of tau lead to a disruption of MT stability; however, direct evidence is lacking in vivo. In this study, an in vivo stable isotope-mass spectrometric technique was used to measure the turnover, or dynamicity, of MTs in brains of living animals. We demonstrated an age-dependent increase in MT dynamics in two different tau transgenic mouse models, 3xTg and rTg4510. MT hyperdynamicity was dependent on tau expression, since a reduction of transgene expression with doxycycline reversed the MT changes. Treatment of rTg4510 mice with the epothilone, BMS-241027, also restored MT dynamics to baseline levels. In addition, MT stabilization with BMS-241027 had beneficial effects on Morris water maze deficits, tau pathology, and neurodegeneration. Interestingly, pathological and functional benefits of BMS-241027 were observed at doses that only partially reversed MT hyperdynamicity. Together, these data suggest that tau-mediated loss of MT stability may contribute to disease progression and that very low doses of BMS-241027 may be useful in the treatment of AD and other tauopathies. [ABSTRACT FROM AUTHOR]