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.

Oleuropein aglycone protects against pyroglutamylated-3 amyloid-ß toxicity: biochemical, epigenetic and functional correlates

“…Although the plaques are widely considered as the main contributors to the functional alterations and behavioral deficits that characterize AD (Haass, 2004), several lines of evidence point to a key role played by the early oligomeric Aß aggregates preceding the appearance of mature fibrils and/or possibly leaked from the latter (Hayden and Teplow, 2013). Oligomeric tau aggregates and hyperphosphorylated tau tangles (Barten et al, 2012;Gendron and Petrucelli, 2009) together with the effects of Aß peptides on tau phosphorylation state and degradation are also increasingly considered (Giacobini and Gold, 2013), leading to include AD among the tauopathies (Wang and Liu, 2008).…”

Cerebrospinal fluid–based kinetic biomarkers of axonal transport in monitoring neurodegeneration

“…Data from cell cultures and preclinical models suggest that abnormal microtubule (MT) dynamics and MT-based neuronal transport may play a role (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19). The recent development of an in vivo stable isotope-mass spectrometric technique for measuring the turnover of MTs provides insights regarding neurodegeneration (14)(15)(16)(17). The measurements revealed that hyperdynamic MTs underlie impairment of MT-based axonal transport in mice expressing the ALS-linked mutant SOD1 G93A (15) and cognitive deficits in AD mice or other models of neurodegeneration (16,17).…”

“…The recent development of an in vivo stable isotope-mass spectrometric technique for measuring the turnover of MTs provides insights regarding neurodegeneration (14)(15)(16)(17). The measurements revealed that hyperdynamic MTs underlie impairment of MT-based axonal transport in mice expressing the ALS-linked mutant SOD1 G93A (15) and cognitive deficits in AD mice or other models of neurodegeneration (16,17). Moreover, MT-modulating pharmacotherapy proved effective at delaying disease progression and increasing neuronal survival (15)(16)(17).…”

Possible Treatments of Atypical Parkinsonism

“…In particular, taxanes, a class of cancer drugs and a related class of compounds called epothilones, are now being investigated as tau-related neurodegeneration. The epothilone D was found to improve axonal microtubule density and improved spatial learning in treated mice [38,39]. It has been suggested that mitochondrial dysfunction may contribute to pathogenesis of atypical parkinsonisms.…”