Neurodegenerative tauopathies, which include Alzheimer's disease (AD), arecharacterized by the presence of insoluble aggregates comprised of hyperphosphorylatedtau proteins. Tau is an endogenous MT-stabilizing agent that is highly expressed in theaxons of neurons. The MT-stabilizing function of tau is essential for the axonal transportof proteins, neurotransmitters and other cellular constituents. Under pathologicalconditions, tau becomes sequestered into insoluble aggregates and no longer can bind toand stabilize MTs. This phenomenon triggers axonal transport deficits with deleteriousconsequences for the affected neurons. As a result, one potential strategy for thetreatment of AD and related tauopathies is to employ brain-penetrant MT-stabilizingagents that could restore/maintain an effective axonal transport machinery bycompensating for the loss of normal tau function. Toward this end, comparativepharmacokinetic studies involving MT-stabilizing agents from different classes of naturalproducts identified epothilone D (EpoD) as a promising candidate. In a preventativestudy with tau transgenic mice (PS19), weekly doses of EpoD (1 or 3 mg/kg, i.p.) for aperiod of 3 months resulted in improved MT-density, axonal integrity and cognition incompound-treated animals, without overt signs of side-effects. Equally important, similaroutcome was observed in an interventional study in which weekly doses of EpoD (0.3 or1 mg/kg, i.p.) were administered to aged PS19 mice with existing tau pathology.Collectively, these results suggest that brain-penetrant MT-stabilizing agents holdpromise for the treatment of AD and related tauopathies.

Microtubule-stabilizing agents as potential treatment for Alzheimer's disease and related tauopathies

243rd National Meeting (2012)

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