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PMID: 19184068 Published · ppublish English Journal Article Review

Mechanisms of tau-induced neurodegeneration.

Acta neuropathologica ·Vol. 118 ·No. 1 ·2009-07-00 ·Pages 53-69

Iqbal K, Liu F, Gong CX, Alonso Adel C, Grundke-Iqbal I

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.

MeSH Terms
Alzheimer Disease/metabolism,pathology Amyloid beta-Peptides/metabolism Animals Brain/metabolism,pathology Dementia/genetics,physiopathology Down Syndrome/physiopathology Endoplasmic Reticulum, Rough/metabolism Glucose/metabolism Humans Microtubule-Associated Proteins/metabolism Microtubules/metabolism Mutation Nerve Degeneration Neurofibrillary Tangles/physiology Phosphorylation Protein Conformation Tauopathies/metabolism,pathology tau Proteins/genetics,metabolism
Chemicals
Amyloid beta-Peptides MAPT protein, human Microtubule-Associated Proteins tau Proteins Glucose
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Iqbal Khalid
Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, Staten Island, NY, 10314, USA, khalid.iqbal.ibr@gmail.com.
Liu Fei
Gong Cheng-Xin
Alonso Alejandra Del C
Grundke-Iqbal Inge
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Article Info
Journal
Acta neuropathologica
Abbr.
Acta Neuropathol
ISSN
1432-0533
DOI
10.1007/s00401-009-0486-3
Email
khalid.iqbal.ibr@gmail.com
Published
2009-07-00
Epub
2009-00-30
Pages
53-69
Language
English
Region
Germany
NLM ID
0412041
PMCID
PMC2872491
Subset
IM
Grants
NIA NIH HHS · R01 AG028538-05 · United States
NIA NIH HHS · R01 AG027429 · United States
NIA NIH HHS · R01 AG019158 · United States
NIA NIH HHS · R01 AG019158-08 · United States
NIA NIH HHS · R01 AG028538 · United States
NIA NIH HHS · R01 AG028538-03 · United States
External Links
PubMed source DOI: 10.1007/s00401-009-0486-3 PMC Full Text View journal details
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