Activation of tau protein kinase I/glycogen synthase kinase-3β by amyloid β peptide (25–35) enhances phosphorylation of tau in hippocampal neurons
Abstract
According to the amyloid hypothesis for the pathogenesis of Alzheimer's disease (AD), amyloid beta peptide (Abeta) directly affects neurons, leading to neurodegeneration and tau phosphorylation, followed by the production of paired helical filaments (PHF) in neurofibrillary tangles (NFT). To analyze the relationship between the phosphorylation sites of tau and the activation of kinases in response to Abeta, we treated cultured rat hippocampal neurons with a peptide fragment of Abeta, Abeta(25-35). Abeta(25-35) treatment activated tau protein kinase I/glycogen synthase kinase-3beta (TPKI/GSK-3beta) but not glycogen synthase kinase-3alpha (GSK-3alpha) or mitogen activated protein kinase (MAP kinase) in primary culture of hippocampal neurons. Using antibodies that recognize phosphorylated sites of tau, we showed that tau phosphorylation was enhanced in at least five sites (Ser199, Ser202, Ser396, Ser404, and Ser413 numbered according to the human tau isoform containing 441 amino acid residues), to an extent that depended on the level of TPK I/GSK-3beta. Treatment with TPK I/GSK-3beta antisense oligonucleotide inhibited the enhancement of tau phosphorylation induced by Abeta(25-35) exposure. Thus, TPK I/GSK-3beta activation by Abeta(25-35) may lead to extensive tau phosphorylation.
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In cellular and animal models, co-expression of Aβ augments tau phosphorylation at these sites and increases the levels of active GSK3 and PAR-1/MARK.
“In cellular and animal models, co-expression of Aβ augments tau phosphorylation at these sites and increases the levels of active GSK3 and PAR-1/MARK [2, 35–41, 43, 44].”
Activities of GSK3 and PAR-1/MARKs are often associated with tau detachment from microtubules and Aβ-induced augmentation of tau toxicity.
“the activities of two major tau kinases, GSK3 and PAR-1/microtubule affinity-regulating kinases (MARKs), are often associated with tau detachment from microtubules and Aβ-induced augmentation of tau toxicity [37, 39, 43–45].”
Aβ promotes tau phosphorylation at disease-associated sites in in vitro and in vivo models of AD.
“Aβ promotes tau phosphorylation at disease-associated sites in in vitro and in vivo models of AD [2, 35–41].”
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- Authors
- Takashima, A., Honda, T., Yasutake, K., Michel, G., Murayama, O., Murayama, M., Ishiguro, K., & Yamaguchi, H.
- Affiliations
- Gunma University (JP)
- Corresponding author
- Takashima, Akihiko
- Venue
- Neuroscience Research
- Publisher
- Elsevier BV
- Published
- 1998-08
- Volume
- 31
- Issue
- 4
- Pages
- 317-323
- ISSN
- 0168-0102 (ISSN-L)
- OpenAlex
- W2058085247
- Cited by
- 287
- References
- 3
- Citations by year
- 2026: 3 · 2025: 6 · 2024: 4 · 2023: 8 · 2022: 4 · 2021: 7 · 2020: 9 · 2019: 4 · 2018: 5 · 2017: 13 · 2016: 8 · 2015: 10 · 2014: 16 · 2013: 14 · 2012: 15
- FWCI
- 3.88
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neuroscience Research (publishedVersion)
- PubMed (publishedVersion)
- 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
- glycogen synthase kinase-3β, amyloid beta 25-35, tau phosphorylation, hippocampal neurons, Alzheimer's disease, amyloid hypothesis, neurofibrillary tangles, paired helical filaments, antisense oligonucleotides, mitogen-activated protein kinase, GSK3α
- MeSH terms
- Animals, Antibodies, Cells, Cultured, Enzyme Activation, Hippocampus, Microtubule-Associated Proteins, Neurons, Peptide Fragments, Phosphorylation, Gene Expression Regulation, Enzymologic, Amyloid beta-Peptides, Antisense Elements (Genetics), tau Proteins, Protein Serine-Threonine Kinases, Calcium-Calmodulin-Dependent Protein Kinases, Glycogen Synthase Kinases, Glycogen Synthase Kinase 3, Rats
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