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Microtubule-Stabilizing Agents for Alzheimer’s and Other Tauopathies

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Book cover Alzheimer’s Disease II

Part of the book series: Topics in Medicinal Chemistry ((TMC,volume 24))

Abstract

In neurodegenerative tauopathies, of which the most prevalent example is Alzheimer’s disease (AD), the aggregation of the microtubule (MT)-stabilizing protein tau is believed to have neuropathological consequences. Multiple studies indicate that deficits in axonal MTs and axonal transport may contribute to the neurodegenerative processes of these diseases. MT-stabilizing molecules have shown promise in restoring axonal MTs and transport, as well as cognitive performance, in animal models of human tauopathies. As a result, such compounds may be considered as potential candidates for the treatment of AD and related tauopathies. Many examples of MT-stabilizing natural products and derivatives thereof have been approved for cancer treatment; however, the use of these compounds for central nervous system (CNS) diseases may be challenging due to limited brain penetration and oral bioavailability, as well as potential systemic side effects. In this chapter, we review the progress made toward the identification and development of CNS-active MT-stabilizing candidate compounds, with an emphasis on nonnaturally occurring small molecules that exhibit favorable drug-like properties.

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Acknowledgments

These studies were supported by NIH grants AG17586, AG029213, and AG044332. We would also like to acknowledge the generous donations made by the Karen Cohen Segal and Christopher S. Segal Alzheimer Drug Discovery Initiative Fund, the Paula C. Schmerler Fund for Alzheimer’s Research, the Barrist Neurodegenerative Disease Research Fund, the Eleanor Margaret Kurtz Endowed Fund, the Mary Rasmus Endowed Fund for Alzheimer’s Research, and Mrs. Gloria J. Miller and Arthur Peck, M.D., the Wood Foundation.

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Authors and Affiliations

  1. Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, MC0756, La Jolla, CA, 92093, USA

    Carlo Ballatore

  2. Department of Chemistry, School of Arts and Sciences, University of Pennsylvania, 231 South 34th Street, Philadelphia, PA, 19104-6323, USA

    Amos B. Smith III

  3. Center for Neurodegenerative Disease Research, Institute on Aging, University of Pennsylvania, 3600 Spruce Street, Philadelphia, PA, 19104-6323, USA

    Virginia M.-Y. Lee, John Q. Trojanowski & Kurt R. Brunden

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  1. Carlo Ballatore
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  2. Amos B. Smith III
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  3. Virginia M.-Y. Lee
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  4. John Q. Trojanowski
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  5. Kurt R. Brunden
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Correspondence to Carlo Ballatore or Kurt R. Brunden .

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  1. Department of Medicinal Chemistry, University of Kansas , Lawrence, Kansas, USA

    Michael S. Wolfe

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Ballatore, C., Smith, A.B., Lee, V.MY., Trojanowski, J.Q., Brunden, K.R. (2016). Microtubule-Stabilizing Agents for Alzheimer’s and Other Tauopathies. In: Wolfe, M. (eds) Alzheimer’s Disease II. Topics in Medicinal Chemistry, vol 24. Springer, Cham. https://doi.org/10.1007/7355_2016_15

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