Cytoskeletal integrity as a drug target

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 tau and evidence that the toxic amyloid peptides in AD can lead to tau 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 Abeta 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.