Inhibition of neurofibrillary degeneration: a promising approach to Alzheimer's disease and other tauopathies.
Neurofibrillary degeneration (ND) is both a pivotal and a primary lesion of Alzheimer disease (AD) and related tauopathies. To date in all known tauopathics including AD, the neurofibrillary changes, whether of paired helical filaments (PHF), twisted ribbons or straight filaments (SF) are made up of abnormally hyperphosphorylated tau, and the number of these lesions directly correlates to the degree of dementia in the affected individuals. Unlike normal tau which promotes assembly and maintains structure of microtubules, the abnormal tau not only lacks these functions but also sequesters normal tau, MAPI and MAP2, and causes disassembly of microtubules. This toxic behavior of the abnormal tau is solely due to its hyperphosphorylation because dephosphorylation restores it into a normal-like protein. The abnormal hyperphosphorylation also promotes the self-assembly of tau into PHF/SF. Missense mutations in tau that cosegregate with the disease in inherited cases of frontotemporal dementia make it a more favorable substrate for hyperphosphorylation. A cause of the abnormal hyperphosphorylation in AD brain is a decrease in the activity of protein phosphatase (PP)-2A, a major regulator of the phosphorylation of tau. The abnormal hyperphosphorylation of tau and neurofibrillary degeneration may be inhibited by increasing the activity of PP-2A, inhibiting the activity of one or more tau kinases or by the sequestration of normal tau by the abnormally hyperphosphorylated tau. A great advantage of developing therapeutic drugs to inhibit neurofibrillary degeneration is that the efficacy of these drugs can be monitored by assaying the CSF levels of phosphotau and total tau, both of which are elevated in AD. Thus, the development of drugs that inhibit neurofibrillary degeneration is a very promising and feasible therapeutic approach to AD and related tauopathies.
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Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, Staten Island, New York 10314-6399, USA. iqbalk@worldnet.att.net
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D000544:Alzheimer Disease / Q000517:prevention & control; D016503:Drug Delivery Systems / Q000379:methods / Q000639:trends; D006801:Humans; D016874:Neurofibrillary Tangles / Q000187:drug effects* / Q000473:pathology / Q000648:ultrastructure; D024801:Tauopathies / Q000188:drug therapy / Q000209:etiology / Q000517:prevention & control*