Barten DM, Fanara P, Andorfer C, Hoque N, Wong PY, Husted KH, Cadelina GW, Decarr LB, Yang L, Liu V, Fessler C, Protassio J, Riff T, Turner H, Janus CG, Sankaranarayanan S, Polson C, Meredith JE, Gray G, Hanna A, Olson RE, Kim SH, Vite GD, Lee FY, Albright CF. Hyperdynamic microtubules, cognitive deficits, and pathology are improved in tau transgenic mice with low doses of the microtubule-stabilizing agent BMS-241027. J Neurosci. 2012 May 23;32(21):7137-45. PubMed.
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Deceased
One curious point about this drug, epothilone D, is that the drug is so effective at cutting down pathology, even under circumstances where there is little evidence for microtubule stabilization. If this was its mechanism of action, one might expect better cell survival, but it's hard to work out why there would be reduced tau pathology. Somehow, epothilone D seems to prevent and maybe even reverse tau pathology. It probably does this by binding to microtubules—its affinity for microtubules is very high. But it is far from obvious how this would affect the aggregation of tau, or enhance tau clearance.
Regardless of the details of the mechanism, it would seem that Epo D should make it into clinical trials in tau mutation cases, at least the P301L and other amino acid-altering mutations. I have always been curious how to explain the FTD that results from mutations in the splice junction of exon 10 of tau. These mutations increase the amount of 4R tau compared to 3R tau, and have a phenotype similar to the P301L mutation. However, since 4R tau is supposed to be more effective at stabilizing microtubules than 3R tau, why is the change in ratio so toxic?
Case Western Reserve University
Coming hard on the heels of the work by Brunden and colleagues (Zhang et al., 2012), this study further strengthens the validity of microtubules as a therapeutic target for the treatment of AD. Although most of the preclinical data are obtained by studying mutant tau transgenic mouse models, it is highly likely that the microtubule-stabilizing drug epothilone D (BMS-241027), since it also reduces tau pathology, will be protective in AD mouse models.
One curious suggestion of this study is that the cognitive benefits of epothilone D may be independent of its microtubule stabilization effect. The observation that administration of a total 8 mg/kg of epothilone D over an eight-week period did not stabilize the microtubules (but showed cognitive improvements), whereas administration of just 1.1 mg of epothilone D over an 11-week period resulted in increased microtubule stability (no behavioral data are presented for this dosage), indicates that biological effects of epothilone D are complex. This should not be surprising, since the better characterized microtubule stabilizer paclitaxel, which is similar to epothilone D, also exerts pleiotropic effects, including anti-inflammatory immunomodulatory activity (Mullins et al., 1997; Hellal et al., 2011).
A potential attraction of the microtubule/tau-focused therapy is that, unlike amyloid-based approaches, this strategy is likely to be effective at later stages of disease when microtubule dysfunction causes defective axonal trafficking, altered mitochondrial metabolism and impaired autophagic degradation leading to deterioration in neuronal functioning. Drugs that restore microtubule function are likely to reduce these multiple deleterious events and improve overall neuronal functioning. It remains to be seen how effective the microtubule-focused strategy will be clinically. Nonetheless, it will be a welcome development if such approaches are fast-tracked into clinical trials.
References:
Zhang B, Carroll J, Trojanowski JQ, Yao Y, Iba M, Potuzak JS, Hogan AM, Xie SX, Ballatore C, Smith AB, Lee VM, Brunden KR. The microtubule-stabilizing agent, epothilone D, reduces axonal dysfunction, neurotoxicity, cognitive deficits, and Alzheimer-like pathology in an interventional study with aged tau transgenic mice. J Neurosci. 2012 Mar 14;32(11):3601-11. PubMed.
Mullins DW, Walker TM, Burger CJ, Elgert KD. Taxol-mediated changes in fibrosarcoma-induced immune cell function: modulation of antitumor activities. Cancer Immunol Immunother. 1997 Oct;45(1):20-8. PubMed.
Hellal F, Hurtado A, Ruschel J, Flynn KC, Laskowski CJ, Umlauf M, Kapitein LC, Strikis D, Lemmon V, Bixby J, Hoogenraad CC, Bradke F. Microtubule stabilization reduces scarring and causes axon regeneration after spinal cord injury. Science. 2011 Feb 18;331(6019):928-31. PubMed.
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