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Alzheimer neurofibrillary degeneration

Therapeutic targets and high-throughput assays

  • Alzheimer’s Therapeutics: Anti-Tangle
  • Published:
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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.

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Authors and Affiliations

  1. New York State Institute for Basic Research in Developmental Disabilities, 10314-6399, Staten Island, New York

    Khalid Iqbal, Alejandra del C. Alonso, Ezzat El-Akkad, Cheng-Xin Gong, Niloufar Haque, Sabiha Khatoon, Hitoshi Tanimukai, Ichiro Tsujio, Jian-Zhi Wang & Inge Grundke-Iqbal

  2. Division of Experimental Geriatrics, Novum, Karolinska Institute, NEUROTEC, Huddinge, Sweden

    Jin-Jing Pei

  3. Department of Pathophysiology, Tongji Medical College, Wuhan, Hubei, P.R. China

    Jian-Zhi Wang

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  1. Khalid Iqbal
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  2. Alejandra del C. Alonso
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  3. Ezzat El-Akkad
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  11. Inge Grundke-Iqbal
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Correspondence to Khalid Iqbal.

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Iqbal, K., Alonso, A.d.C., El-Akkad, E. et al. Alzheimer neurofibrillary degeneration. J Mol Neurosci 20, 425–429 (2003). https://doi.org/10.1385/JMN:20:3:425

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  • DOI: https://doi.org/10.1385/JMN:20:3:425

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