Tau pathology in Alzheimer disease and other tauopathies

Iqbal, Khalid; del C. Alonso, Alejandra; Chen, She; Chohan, M. Omar; El-Akkad, Ezzat; Gong, Cheng-Xin; Khatoon, Sabiha; Li, Bin; Liu, Fei; Rahman, Abdur; Tanimukai, Hitoshi; Grundke-Iqbal, Inge

doi:10.1016/j.bbadis.2004.09.008

Cited by 1,037Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

Tau pathology in Alzheimer disease and other tauopathies

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Iqbal, Khalid, del C. Alonso, Alejandra, Chen, She, Chohan, M. Omar, El-Akkad, Ezzat, Gong, Cheng-Xin, Khatoon, Sabiha, Li, Bin +4 more·2005·Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease

DOI 10.1016/j.bbadis.2004.09.008

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Abstract

Just as neuronal activity is essential to normal brain function, microtubule-associated protein tau appears to be critical to normal neuronal activity in the mammalian brain, especially in the evolutionary most advanced species, the homo sapiens. While the loss of functional tau can be compensated by the other two neuronal microtubule-associated proteins, MAP1A/MAP1B and MAP2, it is the dysfunctional, i.e., the toxic tau, which forces an affected neuron in a long and losing battle resulting in a slow but progressive retrograde neurodegeneration. It is this pathology which is characteristic of Alzheimer disease (AD) and other tauopathies. To date, the most established and the most compelling cause of dysfunctional tau in AD and other tauopathies is the abnormal hyperphosphorylation of tau. The abnormal hyperphosphorylation not only results in the loss of tau function of promoting assembly and stabilizing microtubules but also in a gain of a toxic function whereby the pathological tau sequesters normal tau, MAP1A/MAP1B and MAP2, and causes inhibition and disruption of microtubules. This toxic gain of function of the pathological tau appears to be solely due to its abnormal hyperphosphorylation because dephosphorylation converts it functionally into a normal-like state. The affected neurons battle the toxic tau both by continually synthesizing new normal tau and as well as by packaging the abnormally hyperphosphorylated tau into inert polymers, i.e., neurofibrillary tangles of paired helical filaments, twisted ribbons and straight filaments. Slowly but progressively, the affected neurons undergo a retrograde degeneration. The hyperphosphorylation of tau results both from an imbalance between the activities of tau kinases and tau phosphatases and as well as changes in tau's conformation which affect its interaction with these enzymes. A decrease in the activity of protein phosphatase-2A (PP-2A) in AD brain and certain missense mutations seen in frontotemporal dementia promotes the abnormal hyperphosphorylation of tau. Inhibition of this tau abnormality is one of the most promising therapeutic approaches to AD and other tauopathies.

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CDK5 and GSK3β have been most implicated in the abnormal hyperphosphorylation of tau.
“Among the several kinases involved in tau hyperphosphorylation (Singh et al., 1994;Johnson and Hartigan, 1999), CDK5 and GSK3␤ have been most implicated in the abnormal hyperphosphorylation of tau (Imahori and Uchida, 1997;Shelton and Johnson, 2004;Iqbal et al., 2005).”
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Tau in Alzheimer Disease and Related Tauopathies
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Authors: Iqbal, K., del C. Alonso, A., Chen, S., Chohan, M. O., El-Akkad, E., Gong, C.-X., Khatoon, S., Li, B., Liu, F., Rahman, A., Tanimukai, H., & Grundke-Iqbal, I.
Affiliations: New York State Office for People With Developmental Disabilities (US)
Corresponding author: Iqbal, Khalid
ORCID: Iqbal, Khalid
Chohan, M. Omar
Gong, Cheng-Xin
Khatoon, Sabiha
Liu, Fei
Rahman, Abdur
Tanimukai, Hitoshi
Venue: Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease
Publisher: Elsevier BV
Published: 2005-01
Volume: 1739
Issue: 2-3
Pages: 198-210
ISSN: 0925-4439 (ISSN-L)
DOI: 10.1016/j.bbadis.2004.09.008
OpenAlex: W1998440070
Cited by: 1,037
References: 154
Citations by year: 2026: 28 · 2025: 48 · 2024: 50 · 2023: 67 · 2022: 60 · 2021: 60 · 2020: 57 · 2019: 58 · 2018: 64 · 2017: 48 · 2016: 48 · 2015: 54 · 2014: 52 · 2013: 48 · 2012: 52
FWCI: 3.38
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 3120 d)
Locations: Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease (publishedVersion)
PubMed (publishedVersion)
Funders: National Institutes of Health
National Institute on Aging (AG19158, R01AG019158)
Topics: Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords: tau protein, tauopathy, Alzheimer's disease, tau hyperphosphorylation, neurofibrillary tangles, paired helical filaments, microtubule stabilization, MAP2, tau kinases, protein phosphatase 2A, frontotemporal dementia, tau conformation, neurodegeneration, tau dephosphorylation, tau-targeted therapy
MeSH terms: Alzheimer Disease, Brain, Enzyme Inhibitors, Humans, Models, Biological, Nerve Degeneration, Neurofibrils, Phosphoprotein Phosphatases, Phosphorylation, Protein Conformation, Protein Kinases, Neurofibrillary Tangles, tau Proteins, Tauopathies, Protein Phosphatase 2

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