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Acta Neuropathologica

, Volume 118, Issue 1, pp 53–69 | Cite as

Mechanisms of tau-induced neurodegeneration

  • Khalid IqbalEmail author
  • Fei Liu
  • Cheng-Xin Gong
  • Alejandra del C. Alonso
  • Inge Grundke-Iqbal
Review

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.

Keywords

Alzheimer disease Tauopathies Microtubule associated proteins Abnormally hyperphosphorylated tau Protein phosphatase-2A Neurofibrillary pathology 

Abbreviations

AD

Alzheimer disease

PHF

Paired helical filaments

SF

Straight filaments

Notes

Acknowledgments

We are grateful to Janet Murphy for secretarial assistance. Studies in our laboratories were supported in part by the New York State Office of Mental Retardation and Developmental Disabilities and NIH grants AG019158, AG028538, and AG27429, and Alzheimer’s Association (Chicago, IL) grants IIRG-00-2002, IIRG-05-13095, and NIRG-08-91126.

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Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Khalid Iqbal
    • 1
    Email author
  • Fei Liu
    • 1
  • Cheng-Xin Gong
    • 1
  • Alejandra del C. Alonso
    • 2
  • Inge Grundke-Iqbal
    • 1
  1. 1.Department of NeurochemistryNew York State Institute for Basic Research in Developmental DisabilitiesStaten IslandUSA
  2. 2.Department of Biology and Program in Developmental NeuroscienceThe College of Staten IslandStaten IslandUSA

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