Abstract
Neurofibrillary tangles (NFTs) are a distinguishing neuropathological feature found in postmortem brains of Alzheimers 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
Current Topics in Medicinal Chemistry
Title: Tau Protein Phosphorylation as a Therapeutic Target in Alzheimers Disease
Volume: 2 Issue: 4
Author(s): Lit-fui Lau, Joel B. Schachter, Patricia A. Seymour and Mark A. Sanner
Affiliation:
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
Abstract: Neurofibrillary tangles (NFTs) are a distinguishing neuropathological feature found in postmortem brains of Alzheimers 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.
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Cite this article as:
Lau Lit-fui, Schachter B. Joel, Seymour A. Patricia and Sanner A. Mark, Tau Protein Phosphorylation as a Therapeutic Target in Alzheimers Disease, Current Topics in Medicinal Chemistry 2002; 2 (4) . https://dx.doi.org/10.2174/1568026024607526
DOI https://dx.doi.org/10.2174/1568026024607526 |
Print ISSN 1568-0266 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4294 |
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