Cytoskeletal Integrity as a Drug Target

Authors: Michaelis, M. L.; Seyb, K. I.; Ansar, S.

Source: Current Alzheimer Research, Volume 2, Number 2, April 2005 , pp. 227-229(3)

Publisher: Bentham Science Publishers

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Abstract:

The cytoskeleton provides structural integrity and determines localization of proteins and organelles throughout the cell. The focus on structure and transport has overshadowed the role this ubiquitous network plays in cell signaling cascades, though it participates in transduction of signals from the plasma membrane to the nucleus. Clearly the discovery that neurofibrillary tangles (NFTs) in Alzheimer's disease (AD) brain are made up of the microtubule (MT)-associated protein tgr

and evidence that the toxic amyloid peptides in AD can lead to tgr

hyper-phosphorylation and cytoskeletal dystrophy support the assertion that disruption of the MT network is an early signaling event in neurodegenerative cascades. Thus we have been testing the hypothesis that drugs that can moderate such signals through interactions with MTs would protect neurons against A bgr

toxicity. Drugs targeted to MTs are currently used as anti-cancer agents, due to their blockade of cell proliferation and induction of cell death. However, we and others have now found that low concentrations of compounds that help stabilize MTs do indeed protect post-mitotic neurons challenged with various toxic stimuli. Therefore we propose that the cytoskeletal network actually serves as a sensor for the overall state of the neurons and a first-line transducer of stress signals. Drugs that can moderate initiation of such early signaling events do protect against disruption of the cytoskeleton and neuritic dystrophy in neuronal cell cultures. In vivo proof-of-concept studies in animal models will require the development of agents that can protect cytoskeletal integrity and also cross the blood brain barrier.

Keywords: microtubules (mts); transduction; signaling pathways; axonal projections; neurofibrillary tangles; alzheimer’s disease (ad); neurodegeneration

Document Type: Review article

DOI: http://dx.doi.org/10.2174/1567205053585837

Affiliations: 1: Department of Pharmacology and Toxicology, 5064 Malott Hall, 1251 Wescoe Drive, University of Kansas, Lawrence, KS 66045, USA.

Publication date: 2005-04-01

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Current Alzheimer Research publishes peer-reviewed frontier review and research articles on all areas of Alzheimer's disease. This multidisciplinary journal will help in understanding the neurobiology, genetics, pathogenesis, and treatment strategies of Alzheimer's disease. The journal publishes objective reviews written by experts and leaders actively engaged in research using cellular, molecular, and animal models. The journal also covers original articles on recent research in fast emerging areas of molecular diagnostics, brain imaging, drug development and discovery, and clinical aspects of Alzheimer's disease. Manuscripts are encouraged that relate to the synergistic mechanism of Alzheimer's disease with other dementia and neurodegenerative disorders. Book reviews, meeting reports and letters-to-the-editor are also published. The journal is essential reading for researchers, educators and physicians with interest in age-related dementia and Alzheimer's disease. Current Alzheimer Research provides a comprehensive 'bird's-eye view' of the current state of Alzheimer's research for neuroscientists, clinicians, health science planners, granting, caregivers and families of this devastating disease.

Cytoskeletal Integrity as a Drug Target

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