Authors: Iqbal, Khalid¹; Alonso, Alejandra²; El-Akkad, Ezzat²; Gong, Cheng-Xin²; Haque, Niloufar²; Khatoon, Sabiha²; Pei, Jin-Jing³; Tanimukai, Hitoshi²; Tsujio, Ichiro²; Wang, Jian-Zhi²; Inge, Grundke-Iqbal²

Source: Journal of Molecular Neuroscience, Volume 20, Number 3, August 2003 , pp. 425-429(5)

Publisher: Humana Press

Abstract:

Neurofibrillary degeneration has primary and pivotal involvement in the pathogenesis of Alzheimer disease (AD) and other tauopathies. The inhibition of this lesion offers a promising therapeutic approach. The microtubule-associated protein (MAP) tau is abnormally hyperphosphorylated in the brain of patients with AD, and in this form it is the major protein subunit of paired helical filaments/neurofibrillary tangles (PHF/NFT). The abnormal tau that is polymerized into PHF/NFT is apparently inert and has no effect on microtubule assembly in vitro. The cytosolic abnormally hyperphosphorylated tau from AD brain, the AD P-tau, does not promote in vitro microtubule assembly but, instead, sequesters normal tau, MAP1, and MAP2 and inhibits microtubule assembly. The AD P-tau readily self-assembles in vitro into tangles of PHF/straight filaments, and this self-assembly requires the abnormal hyperphosphorylation of this protein. Although, to date, an up-regulation of the activity of a tau kinase has not been established, the activity of phosphoseryl/phosphothreonyl protein phosphatase (PP)-2A, which regulates the phosphorylation of tau, is compromised in AD brain. Thus, modulation of the activities of pp-2A and one or more tau kinases and inhibition of the sequestration of normal MAPs by ADP-tau offer promising therapeutic opportunities to inhibit neurofibrillary degeneration and the diseases characterized by this lesion. Development of high-throughput screening assays for potential drugs aimed at these therapeutic targets is currently under way.

Keywords: Alzheimer's disease; neurofibrillary degeneration; tauopathies; abnormal hyperphosphorylation; microtubules; tau

Document Type: Research article

DOI: http://dx.doi.org/10.1385/JMN:20:3:425

Affiliations: 1: New York State Institute for Basic Research in Developmental Disabilities, 10314-6399, Staten Island, New York, Email: iqbalk@worldnet.att.net 2: New York State Institute for Basic Research in Developmental Disabilities, 10314-6399, Staten Island, New York, 3: Division of Experimental Geriatrics, Novum, Karolinska Institute, NEUROTEC, Huddinge, Sweden,

Publication date: 2003-08-01

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• In this Subject: Anatomy & Physiology ,  Zoology ,  Neurology & Psychiatry
• By this author: Iqbal, Khalid ;  Alonso, Alejandra ;  El-Akkad, Ezzat ;  Gong, Cheng-Xin ;  Haque, Niloufar ;  Khatoon, Sabiha ;  Pei, Jin-Jing ;  Tanimukai, Hitoshi ;  Tsujio, Ichiro ;  Wang, Jian-Zhi ;  Inge, Grundke-Iqbal

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