Alzheimer neurofibrillary degeneration: therapeutic targets and high-throughput assays

• Published in: Journal of molecular neuroscience Vol. 20; no. 3; pp. 425 - 429
• Main Authors: Iqbal, Khalid, Alonso, Alejandra del C, El-Akkad, Ezzat, Gong, Cheng-Xin, Haque, Niloufar, Khatoon, Sabiha, Pei, Jin-Jing, Tanimukai, Hitoshi, Tsujio, Ichiro, Wang, Jian-Zhi, Grundke-Iqba, Inge
• Format: Journal Article
• Language: English
• Published: United States 2003
• Subjects: Alzheimer Disease - drug therapy; Alzheimer Disease - metabolism; Alzheimer Disease - physiopathology; Animals; Drug Evaluation, Preclinical; Enzyme Inhibitors - pharmacology; Enzyme Inhibitors - therapeutic use; Humans; Medicin och hälsovetenskap; Microtubules - metabolism; Microtubules - pathology; Neurofibrillary Tangles - drug effects; Neurofibrillary Tangles - metabolism; Neurofibrillary Tangles - pathology; Phosphoprotein Phosphatases - drug effects; Phosphoprotein Phosphatases - metabolism; Phosphorylation - drug effects; tau Proteins - drug effects; tau Proteins - metabolism
• ISSN: 0895-8696; 0895-8696
• DOI: 10.1385/JMN:20:3:425

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.