Significance and mechanism of Alzheimer neurofibrillary degeneration and therapeutic targets to inhibit this lesion |
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Authors: | Iqbal Khalid Alonso Alejandra del C El-Akkad Ezzat Gong Cheng-Xin Haque Niloufar Khatoon Sabiha Pei Jin-Jing Tsujio Ichiro Wang Jian-Zhi Grundke-Iqbal Inge |
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Affiliation: | (1) Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, 10314-6399 Staten Island, New York;(2) Division of Experimental Geriatrics, Karolinska Institute, NEUROTEC, Novum, Huddinge, Sweden;(3) Department of Pathophysiology, Tongji Medical College, Wuhan, Hubei, P.R. China |
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Abstract: | Abnormally hyperphosphorylated tau which is the major protein subunit of paired helical filaments (PHF)/neurofibrillary tangles is the pivotal lesion in Alzheimer disease (AD) and related tauopathies. The cosegregation of tau mutations with disease in inherited cases of frontotemporal dementia has confirmed that abnormalities in this protein can be a primary cause of neurodegeneration. Unlike normal tau that promotes assembly and maintains the structure of microtubules, the abnormally hyperphosphorylated protein sequesters normal tau, MAP1 and MAP2 and consequently disassembles microtubules. The abnormal hyperphosphorylation also promotes the self assembly of tau into tangles of PHF. The hyperphosphorylation of tau in AD is probably due to a protein phosphorylation/dephosphorylation imbalance produced by a decrease in the activity of protein phosphatase (PP)-2A and increase in the activities of tau kinases which are directly or indirectly regulated by PP-2A. Two of the most promising pharmacologic therapeutic approaches to AD are (1) the development of drugs that can inhibit the sequestration of normal MAPs by the abnormally hyperphosphorylated tau, and (2) the development of drugs that can reverse the abnormal hyperphosphorylation of tau by correcting the protein phosphorylation/dephosphorylation imbalance. |
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Keywords: | Alzheimer disease microtubule associated protein tau protein phosphatase-2A abnormal hyperphosphorylation neurofibrillary tangles |
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