title: Hyperdynamic microtubules, cognitive deficits, and pathology are improved in tau transgenic mice with low doses of the microtubule-stabilizing agent BMS-241027.
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.
authors.affiliation: Neuroscience Drug Discovery, Bristol-Myers Squibb, Wallingford, Connecticut 06492, USA. donna.barten@bms.com
authors.forename: Donna M
authors.initials: DM
authors.lastname: Barten
authors.forename: Patrizia
authors.initials: P
authors.lastname: Fanara
authors.forename: Cathy
authors.initials: C
authors.lastname: Andorfer
authors.forename: Nina
authors.initials: N
authors.lastname: Hoque
authors.forename: P Y Anne
authors.initials: PY
authors.lastname: Wong
authors.forename: Kristofor H
authors.initials: KH
authors.lastname: Husted
authors.forename: Gregory W
authors.initials: GW
authors.lastname: Cadelina
authors.forename: Lynn B
authors.initials: LB
authors.lastname: Decarr
authors.forename: Ling
authors.initials: L
authors.lastname: Yang
authors.forename: Victoria
authors.initials: V
authors.lastname: Liu
authors.forename: Chancy
authors.initials: C
authors.lastname: Fessler
authors.forename: Joan
authors.initials: J
authors.lastname: Protassio
authors.forename: Timothy
authors.initials: T
authors.lastname: Riff
authors.forename: Holly
authors.initials: H
authors.lastname: Turner
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Janus
authors.forename: Sethu
authors.initials: S
authors.lastname: Sankaranarayanan
authors.forename: Craig
authors.initials: C
authors.lastname: Polson
authors.forename: Jere E
authors.initials: JE
authors.lastname: Meredith
authors.forename: Gemma
authors.initials: G
authors.lastname: Gray
authors.forename: Amanda
authors.initials: A
authors.lastname: Hanna
authors.forename: Richard E
authors.initials: RE
authors.lastname: Olson
authors.forename: Soong-Hoon
authors.initials: SH
authors.lastname: Kim
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Vite
authors.forename: Francis Y
authors.initials: FY
authors.lastname: Lee
authors.forename: Charles F
authors.initials: CF
authors.lastname: Albright
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D003072:Cognition Disorders / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004318:Doxycycline / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical / Q000379:methods / Q000523:psychology; D034261:Epothilones / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008870:Microtubules / Q000187:drug effects / Q000473:pathology*; D009410:Nerve Degeneration / Q000188:drug therapy*; D024801:Tauopathies / Q000150:complications / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology / Q000523:psychology; D050257:Tubulin Modulators / Q000494:pharmacology / Q000627:therapeutic use*; D016875:tau Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*
chemical_list: D034261:Epothilones; D050257:Tubulin Modulators; D016875:tau Proteins; D004318:Doxycycline; C114026:desoxyepothilone B