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Amyloid beta-induced glycogen synthase kinase 3β phosphorylated VDAC1 in Alzheimer's disease: Implications for synaptic dysfunction and neuronal damage
Open accessAbstract
Glycogen synthase kinase 3 (GSK3) is a serine/threonine protein kinase that is involved in the multiple signaling processes of a cell. Increasing evidence suggests that GSK3β plays a key role in multiple cellular processes in the progression of diabetes, obesity, Alzheimer's disease (AD), Parkinson's disease (PD), inflammatory diseases, schizophrenia, bipolar and several mood disorders, and mitochondrial diseases. Recent research has found that increased GSK3β activity is linked to the pathogenesis of AD through amyloid beta (Aβ), phosphorylated tau and mitochondrial dysfunction. Recent research has also revealed that GSK3β is elevated in AD-affected tissues and is critically involved in dissociating the voltage-dependent anion channel 1 (VDAC1) protein from hexokinases, and causing disrupted glucose metabolism, mitochondrial dysfunction and activating apoptotic cell death. The purpose of this article is to review recent research that is elucidating the role of GSK3β in AD pathogenesis. We discuss the involvement of GSK3β in the phosphorylation of VDAC1 and dissociation of VADC1 with hexokinases in AD neurons.
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“GSK3β is already known to be involved in the regulation of APP metabolism, Tau phosphorylation and synaptic functions41–43, making it a potential link between PLCγ2 and the different phenotypes associated with its downregulation.”
From PLCG2 downregulation impairs synaptic function and increases Alzheimer’s disease hallmarks in neuronal cultures (2026) · cites this paper as [41]
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Cedazo-Mı́nguez, Á., Popescu, B. O., Blanco‐Millán, J. M., Akterin, S., Pei, J. ‐., Winblad, B. G., & Cowburn, R. F. (2003) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2003.02088.x · Cited by 99
Ryder, J. W., Yuan, S., & Ni, B. (2003) · Cellular Signalling · doi:10.1016/j.cellsig.2003.07.004 · Cited by 92
The cell cycle as a therapeutic target for Alzheimer's disease
Neve, R. L., & McPhie, D. L. (2006) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2005.09.005 · Cited by 92
Voltage-dependant anion channels: novel insights into isoform function through genetic models
Raghavan, A., Sheiko, T., Graham, B. H., & Craigen, W. J. (2012) · Biochimica et Biophysica Acta (BBA) - Biomembranes · doi:10.1016/j.bbamem.2011.10.019 · Cited by 92
Yamamoto, T., Yamada, A., Watanabe, M., Yoshimura, Y., Yamazaki, N., Yoshimura, Y., Yamauchi, T., Kataoka, M., Nagata, T., Terada, H., et al. (2006) · Journal of Proteome Research · doi:10.1021/pr060291w · Cited by 90
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Glycogen synthase kinase 3 in the world of cell migration
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Al-Sweidi, S., Sánchez, M. G., Bourque, M., Morissette, M., Dluzen, D. E., & Paolo, T. D. (2011) · Journal of Neuroendocrinology · doi:10.1111/j.1365-2826.2011.02193.x · Cited by 82
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Rationale for the Development of Cholinesterase Inhibitors as Anti- Alzheimer Agents
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VDAC proteomics: Post-translation modifications
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Gasparini, L., Ongini, E., Wilcock, D. M., & Morgan, D. (2005) · Brain Research Reviews · doi:10.1016/j.brainresrev.2004.12.029 · Cited by 68
Cholinesterase inhibitors influence APP metabolism in Alzheimer disease patients
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Emerging Roles of Glycogen Synthase Kinase 3 in the Treatment of Brain Tumors
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Flagged first, then by citations
2 of the 133 references couldn’t be matched to a known paper.
Research works printed but not linked: 1
- Jimenez, 2011, J. Biol. Chem., 286, 18414-1825
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Mitochondrial VDAC1: A Key Gatekeeper as Potential Therapeutic Target
Camara, A. K. S., Zhou, Y., Wen, P., Tajkhorshid, E., & Kwok, W.-M. (2017) · Frontiers in Physiology · doi:10.3389/fphys.2017.00460 · Cited by 378
SYK coordinates neuroprotective microglial responses in neurodegenerative disease
Ennerfelt, H., Frost, E. L., Shapiro, D. A., Holliday, C., Zengeler, K. E., Voithofer, G., Bolte, A. C., Lammert, C. R., Kulas, J. A., Ulland, T. K., et al. (2022) · Cell · doi:10.1016/j.cell.2022.09.030 · Cited by 297
“…to contribute to Aβ accumulation, tau phosphorylation, and neuronal damage in models of AD (DaRocha-Souto et al., 2012; Hernandez et al., 2013; Hurtado et al., 2012; Reddy, 2013), SYK-related modulation of the GSK3β pathway may contribute to the exacerbation of disease seen in 5xFAD SykΔMG mice.”
The Akt pathway in oncology therapy and beyond (Review)
Nițulescu, G. M., van de Venter, M., Nițulescu, G., Ungurianu, A., Juzenas, P., Peng, Q., Olaru, O. T., Grădinaru, D., Tsatsakis, A. M., Tsoukalas, D., et al. (2018) · International Journal of Oncology · doi:10.3892/ijo.2018.4597 · Cited by 331
VDAC1, mitochondrial dysfunction, and Alzheimer’s disease
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Parkin-mediated mitophagy in mutant hAPP neurons and Alzheimer's disease patient brains
Ye, X., Sun, X., Starovoytov, V., & Cai, Q. (2015) · Human Molecular Genetics · doi:10.1093/hmg/ddv056 · Cited by 274
Metadata
- Authors
- Reddy, P. H.
- Affiliations
- Oregon National Primate Research Center (US)
- Corresponding author
- Reddy, P. Hemachandra
- Venue
- Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease
- Publisher
- Elsevier BV
- Published
- 2013-12
- Volume
- 1832
- Issue
- 12
- Pages
- 1913-1921
- ISSN
- 0925-4439 (ISSN-L)
- PMC
- PMC3825775
- OpenAlex
- W2077701948
- Cited by
- 147
- References
- 133
- Citations by year
- 2026: 9 · 2025: 13 · 2024: 12 · 2023: 12 · 2022: 16 · 2021: 15 · 2020: 10 · 2019: 12 · 2018: 13 · 2017: 9 · 2016: 5 · 2015: 11 · 2014: 10
- FWCI
- 0.96
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIH (AG028072, AG042178, RR000163)
- Medical Research Foundation of Oregon
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- Alzheimer's disease, glycogen synthase kinase-3β, VDAC1, amyloid-beta, hexokinase, mitochondrial dysfunction, glucose metabolism, synaptic dysfunction, neuronal injury, apoptosis
- MeSH terms
- Glycogen Synthase Kinase 3 beta, Alzheimer Disease, Animals, Humans, Neurons, Phosphorylation, Synapses, Amyloid beta-Peptides, Glycogen Synthase Kinase 3, Voltage-Dependent Anion Channel 1
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