Sulfhydration of AKT triggers Tau-phosphorylation by activating glycogen synthase kinase 3β in Alzheimer’s disease
Open accessAbstract
Significance: It is well known that AKT inactivates glycogen synthase kinase 3β (GSK3β) by increasing its phosphorylation. The inactivation of GSK3β leads to aberrant phosphorylation of Tau, which is a hallmark of Alzheimer’s disease. However, we found that if phosphorylated AKT is sulfhydrated, it will be unable to inactivate GSK3β and subsequently increases Tau phosphorylation. The influence of sulfhydrated AKT on GSK3β and Tau phosphorylation was reversed in a transgenic AKT-KI +/+ mouse, where sulfhydration of AKT residue was mutated to alanine. Thus, AKT-sulfhydration represents a unique posttranslational modification of AKT that can be targeted to suppress phosphorylation of GSK3β and subsequently reduce Tau phosphorylation.
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IL-1β treatment or overexpression exacerbates tau phosphorylation through activation of p38 MAPK and/or GSK-3β in neuron-microglia co-cultures and AD model mice.
“IL-1β treatment or overexpression exacerbates tau phosphorylation through the activation of p38 mitogen-activated protein kinase (MAPK) and/or glycogen synthase kinase-3β (GSK-3β) in neuron–microglia co-cultures [161] and AD model mice [162, 163].”
From Tau and neuroinflammation in Alzheimer’s disease: interplay mechanisms and clinical translation (2023) · cites this paper as [163]
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“However, AKT can be sulfhydrated under inflammatory conditions, which are present in all of the neurodegenerative disorders, including AD, Parkinson’s disease, traumatic brain injury, and multiple sclerosis (57, 58).”
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Tau and neuroinflammation in Alzheimer’s disease: interplay mechanisms and clinical translation
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- Authors
- Sen, T., Saha, P., Jiang, T., & Sen, N.
- Affiliations
- University of Pittsburgh (US)
- Corresponding author
- Sen, Nilkantha
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2020-02-12
- Volume
- 117
- Issue
- 8
- Pages
- 4418-4427
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC7049105
- OpenAlex
- W3006083475
- Cited by
- 68
- References
- 67
- Citations by year
- 2026: 13 · 2025: 7 · 2024: 15 · 2023: 9 · 2022: 13 · 2021: 10 · 2020: 1
- FWCI
- 4.96
- Type
- journal article
- Language
- en
- Update notices
- correction (2021-10-11)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- HHS | NIH | National Institute of Neurological Disorders and Stroke (RO1NS094516)
- HHS | NIH | National Eye Institute (RO1EY025622)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Keywords
- glycogen synthase kinase-3β, tau phosphorylation, Alzheimer's disease, post-translational modification, Akt inactivation
- MeSH terms
- Glycogen Synthase Kinase 3 beta, Alzheimer Disease, Animals, Brain, Female, Humans, Hydrogen Sulfide, Male, Mice, Transgenic, Phosphorylation, Protein Binding, tau Proteins, Amino Acid Motifs, Proto-Oncogene Proteins c-akt, Mice, Interleukin-1beta
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