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Acta Neuropathologica
Published in: Acta Neuropathologica 1/2009

01-07-2009 | Review

Mechanisms of tau-induced neurodegeneration

Authors: Khalid Iqbal, Fei Liu, Cheng-Xin Gong, Alejandra del C. Alonso, Inge Grundke-Iqbal

Published in: Acta Neuropathologica | Issue 1/2009

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Abstract

Alzheimer disease (AD) and related tauopathies are histopathologically characterized by a specific type of slow and progressive neurodegeneration, which involves the abnormal hyperphosphorylation of the microtubule associated protein (MAP) tau. This hallmark, called neurofibrillary degeneration, is seen as neurofibrillary tangles, neuropil threads, and dystrophic neurites and is apparently required for the clinical expression of AD, and in related tauopathies it leads to dementia in the absence of amyloid plaques. While normal tau promotes assembly and stabilizes microtubules, the non-fibrillized, abnormally hyperphosphorylated tau sequesters normal tau, MAP1 and MAP2, and disrupts microtubules. The abnormal hyperphosphorylation of tau, which can be generated by catalysis of several different combinations of protein kinases, also promotes its misfolding, decrease in turnover, and self-assembly into tangles of paired helical and or straight filaments. Some of the abnormally hyperphosphorylated tau ends up both amino and C-terminally truncated. Disruption of microtubules by the non-fibrillized abnormally hyperphosphorylated tau as well as its aggregation as neurofibrillary tangles probably impair axoplasmic flow and lead to slow progressive retrograde degeneration and loss of connectivity of the affected neurons. Among the phosphatases, which regulate the phosphorylation of tau, protein phosphatase-2A (PP2A), the activity of which is down-regulated in AD brain, is by far the major enzyme. The two inhibitors of PP-2A, I 1 PP2A and I 2 PP2A , which are overexpressed in AD, might be responsible for the decreased phosphatase activity. AD is multifactorial and heterogeneous and involves more than one etiopathogenic mechanism.
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Metadata
Title
Mechanisms of tau-induced neurodegeneration
Authors
Khalid Iqbal
Fei Liu
Cheng-Xin Gong
Alejandra del C. Alonso
Inge Grundke-Iqbal
Publication date
01-07-2009
Publisher
Springer-Verlag
Published in
Acta Neuropathologica / Issue 1/2009
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI
https://doi.org/10.1007/s00401-009-0486-3

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