Hyperdynamic Microtubules, Cognitive Deficits, and Pathology Are Improved in Tau Transgenic Mice with Low Doses of the Microtubule-Stabilizing Agent BMS-241027
Neuroscience Drug Discovery, Bristol-Myers Squibb, Wallingford, Connecticut 06492, USA.The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 05/2012; 32(21):7137-45. DOI: 10.1523/JNEUROSCI.0188-12.2012
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.
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- "Support for a loss-of-function mechanism comes from the finding that some mutations associated with FTDP-17 are localized in the microtubule-binding sites of Tau and reduce its ability to promote microtubule stabilization (LeBoeuf et al., 2008; Combs and Gamblin, 2012). Likewise, phosphorylation of Tau has been shown to decrease its microtubule binding affinity (Li et al., 2007; Barten et al., 2012), suggesting that diseaserelated hyperphosphorylation could also result in the loss of normal Tau function (Zhang et al., 2012). Most studies to define Tau activity have been conducted in vitro or have used overexpression assays and therefore authentic physiological functions for Tau are still largely unknown. "
ABSTRACT: Accumulations of Tau, a microtubule-associated protein, into neurofibrillary tangles is a hallmark of Alzheimer's disease and other tauopathies. However, the mechanisms leading to this pathology are still unclear: the aggregates themselves could be toxic or the sequestration of Tau into tangles might prevent Tau from fulfilling its normal functions, thereby inducing a loss of function defect. Surprisingly, the consequences of losing normal Tau expression in vivo are still not well understood, in part due to the fact that Tau knockout mice show only subtle phenotypes, presumably due to the fact that mammals express several MAPs with partially overlapping functions. In contrast, flies express fewer microtubule-associated proteins, with Tau being the only member of the Tau/MAP2/MAP4 family. Therefore, we used Drosophila to address the physiological consequences caused by the loss of Tau. Reducing the levels of fly Tau (dTau) ubiquitously resulted in developmental lethality, whereas deleting Tau specifically in neurons or the eye caused progressive neurodegeneration. Similarly, chromosomal mutations affecting dTau also caused progressive degeneration in both the eye and brain. Although photoreceptor cells initially developed normally in dTau knockdown animals, they subsequently degenerated during late pupal stages whereas weaker dTau alleles caused an age-dependent defect in rhabdomere structure. Expression of wild type human Tau partially rescued the neurodegenerative phenotype caused by the loss ofendogenous dTau, suggesting that the functions of Tau proteins are functionally conserved from flies to humans. © 2014 Wiley Periodicals, Inc. Develop Neurobiol, 2014.
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- "Epothilone D (EpoD), another MSA with a greater brain-penetrant capability than Ptx improves fast axonal transport and cognitive functions in a transgenic animal model already displaying tau pathology at the time of MSA treatment (Zhang et al., 2012). In another study in transgenic mice overexpressing mutant tau, EpoD improved cognitive behavior and reduced MT hyperdynamicity (Barten et al., 2012). In all these studies, MSA restoration of MT integrity improved cognitive functions in the diseased animals. "
ABSTRACT: An important aspect of synaptic plasticity in the brain is axonal transport of essential components such as mitochondria from the soma to the synapse. For uninterrupted transport of cellular cargo down the axon, functional microtubules are required. Altered microtubule dynamics induced by changes in expression of microtubule-associated tau protein affects normal microtubule function and interferes with axonal transport. Here we investigate the effects of the nontaxoid-binding-site microtubule-stabilizing agents peloruside A (PelA) and laulimalide, compared with the taxoid-site-binding agents paclitaxel (Ptx) and ixabepilone, on axonal transport of mitochondria in 1-day-old rat pup cerebral cortical neuron cultures. The differences in effects of these two types of compound on mitochondrial trafficking were specifically compared under conditions of excess tau expression. PelA and laulimalide had no adverse effects on their own on mitochondrial transport compared with Ptx and ixabepilone, which inhibited mitochondrial run length at higher concentrations. PelA, like Ptx, was able to partially reverse the blocked mitochondrial transport seen in ECFP-htau40-overexpressing neurons, although at higher concentrations of microtubule-stabilizing agent, the PelA response was improved over the Ptx response. These results support a neuroprotective effect of microtubule stabilization in maintaining axonal transport in neurons overexpressing tau protein and may be beneficial in reducing the severity of neurodegenerative diseases such as Alzheimer's disease. © 2014 Wiley Periodicals, Inc.
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- "It is noteworthy that both prophylactic and interventional treatments with the MT-stabilizer Epothilone D (EpoD), which is able to pass the blood-brain barrier, improve axonal MT density, reduce axonal dystrophy and alleviate cognitive deficits in transgenic mouse models of tauopathies1920. It has also been shown that the dynamicity of MTs is increased in tau transgenic mice and that treatment with EpoD restores MT dynamics to baseline levels and exerts beneficial effects on behavior, tau pathology and neurodegeneration21. "
ABSTRACT: The role of microtubule (MT) dysfunction in Parkinson's disease is emerging. It is still unknown whether it is a cause or a consequence of neurodegeneration. Our objective was to assess whether alterations of MT stability precede or follow axonal transport impairment and neurite degeneration in experimental parkinsonism induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in C57Bl mice. MPTP induced a time- and dose-dependent increase in fibres with altered mitochondria distribution, and early changes in cytoskeletal proteins and MT stability. Indeed, we observed significant increases in neuron-specific βIII tubulin and enrichment of deTyr tubulin in dopaminergic neurons. Finally, we showed that repeated daily administrations of the MT stabilizer Epothilone D rescued MT defects and attenuated nigrostriatal degeneration induced by MPTP. These data suggest that alteration of ΜΤs is an early event specifically associated with dopaminergic neuron degeneration. Pharmacological stabilization of MTs may be a viable strategy for the management of parkinsonism.