Alzheimer Neurofibrillary Degeneration: Therapeutic Targets and High-Throughput Assays

Autor: Niloufar Haque, Sabiha Khatoon, Hitoshi Tanimukai, Jin-Jing Pei, Cheng-Xin Gong, Ezzat El-Akkad, Jian-Zhi Wang, Inge Grundke-Iqba, Ichiro Tsujio, K. Iqbal, Alejandra del C. Alonso
Rok vydání: 2003
Předmět:
Zdroj: Journal of Molecular Neuroscience. 20:425-430
ISSN: 0895-8696
DOI: 10.1385/jmn:20:3:425
Popis: 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 AD P-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.
Databáze: OpenAIRE
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