Tau Protein Phosphorylation as a Therapeutic Target in Alzheimer's Disease

Authors: Lau, L-f.; Schachter, J.B.; Seymour, P.A.; Sanner, M.A.

Source: Current Topics in Medicinal Chemistry, Volume 2, Number 4, 1 April 2002 , pp. 395-415(21)

Publisher: Bentham Science Publishers

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Abstract:

Neurofibrillary tangles (NFTs) are a distinguishing neuropathological feature found in postmortem brains of Alzheimer's disease (AD) and tauopathy patients. The density of these lesions correlates with severity of AD and their distribution follows a characteristic pattern of expansion as the disease progresses. The principle components of NFTs are highly phosphorylated forms of the microtubule-associated protein, tau. Tau phosphorylation is believed to initiate or facilitate dissociation from microtubules leading to microtubule destabilization, decay of cellular transport properties, and cell death. This review summarizes recent data and prevailing views on the roles of protein kinases and phosphatases in the regulation of tau phosphorylation in vitro and in vivo, taking into account data from human neurodegenerative diseases and from transgenic rodent models. Small molecule inhibitors of tau phosphorylation that serve as important research tools and possibly the basis of potential new therapeutics, are also described. Key challenges in developing effective therapeutic agents include identification of the relevant kinase(s) responsible for aberrant tau phosphorylation in AD, synthesis of inhibitors selectively targeting those kinases and establishment of appropriate animal models.

Keywords: Tau Protein Phosphorylation; alzheimers disease; neurofibrillary tangles nfts; kinase; neurodegenerative diseases; protein kinases; proline-directed protein kinases; gsk tau protein kinase I; olom oucine; roscovitine

Document Type: Review article

DOI: http://dx.doi.org/10.2174/1568026024607526

Publication date: 2002-04-01