Monday, 12 August 2013

Tracking Research: Hyperdynamic Microtubules, Cognitive Deficits, and Pathology Are Improved in Tau Transgenic Mice with Low Doses of the Microtubule-Stabilizing Agent BMS-241027Neuroscience Drug Discovery, Bristol-Myers Squibb, Wallingford, Connecticut 06492,

Hyperdynamic Microtubules, Cognitive Deficits, and Pathology Are Improved in Tau Transgenic Mice with Low Doses of the Microtubule-Stabilizing Agent BMS-241027

Donna M. Barten, Patrizia Fanara, Cathy Andorfer, Nina Hoque, P. Y. Anne Wong, Kristofor H. Husted2, Gregory W. Cadelina, Lynn B. DeCarr1, Ling Yang, Victoria Liu, Chancy Fessler, Joan Protassio, Timothy Riff, Holly Turner, Christopher G. Janus, Sethu Sankaranarayanan, Craig Polson, Jere E. Meredith, Gemma Gray, Amanda Hanna, Richard E. Olson, Soong-Hoon Kim, Gregory D. Vite, Francis Y. Lee, and Charles F. Albright

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.
 Tracking with HVS Image Barnes Maze

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