Selectively silencing GSK-3 isoforms reduces plaques and tangles in mouse models of Alzheimer's disease
Open accessAbstract
Glycogen synthase kinase-3 (GSK-3) is linked to the pathogenesis of Alzheimer's disease (AD), senile plaques (SPs), and neurofibrillary tangles (NFTs), but the specific contributions of each of the GSK-3 α and β isoforms to mechanisms of AD have not been clarified. In this study, we sought to elucidate the role of each GSK-3α and GSK-3β using novel viral and genetic approaches. First, we developed recombinant adeno-associated virus 2/1 short hairpin RNA constructs which specifically reduced expression and activity of GSK-3α or GSK-3β. These constructs were injected intraventricularly in newborn AD transgenic (tg) mouse models of SPs (PDAPP⁺/⁻), both SPs and NFTs (PDAPP⁺/⁻;PS19⁺/⁻), or wild-type controls. We found that knockdown (KD) of GSK-3α, but not GSK-3β, reduced SP formation in PDAPP⁺/⁻ and PS19⁺/⁻;PDAPP⁺/⁻ tg mice. Moreover, both GSK-3α and GSK-3β KD reduced tau phosphorylation and tau misfolding in PS19⁺/⁻;PDAPP⁺/⁻ mice. Next, we generated triple tg mice using the CaMKIIα-Cre (α-calcium/calmodulin-dependent protein kinase II-Cre) system to KD GSK-3α in PDAPP⁺/⁻ mice for further study of the effects of GSK-3α reduction on SP formation. GSK-3α KD showed a significant effect on reducing SPs and ameliorating memory deficits in PDAPP⁺/⁻ mice. Together, the data from both approaches suggest that GSK-3α contributes to both SP and NFT pathogenesis while GSK-3β only modulates NFT formation, suggesting common but also different targets for both isoforms. These findings highlight the potential importance of GSK-3α as a possible therapeutic target for ameliorating behavioral impairments linked to AD SPs and NFTs.
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GSK3β activation has been shown to contribute to Aβ accumulation, tau phosphorylation, and neuronal damage in models of AD.
“Given that GSK3β activation has been shown 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.”
From SYK coordinates neuroprotective microglial responses in neurodegenerative disease (2022) · cites this paper as Hurtado et al., 2012
The Results section reports that GSK-3β knockdown reduced pathological tau phosphorylation in AD-model mice. But the Results and Discussion distinguish the isoforms: GSK-3α knockdown, not GSK-3β knockdown, reduced Aβ levels and plaque load. The cited passages do not establish a GSK-3β-specific contribution to neuronal damage; no page numbers are available in our copy. (LLM, conf=0.90)
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“Moreover, recent data exploring the specific contributions of each of the GSK3 α and β isoforms in AD disease progression has been described using selective viral and gene silencing techniques in transgenic mouse models of AD (21).”
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- Authors
- Hurtado, D. E., Molina-Porcel, L., Carroll, J. C., MacDonald, C., Aboagye, A. K., Trojanowski, J. Q., & Lee, V. M.-Y.
- Affiliations
- University of Pennsylvania (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2012-05-23
- Volume
- 32
- Issue
- 21
- Pages
- 7392-7402
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC3368584
- OpenAlex
- W2044098401
- Cited by
- 126
- References
- 47
- Citations by year
- 2026: 4 · 2025: 12 · 2024: 7 · 2023: 9 · 2022: 6 · 2021: 10 · 2020: 8 · 2019: 9 · 2018: 6 · 2017: 4 · 2016: 7 · 2015: 9 · 2014: 13 · 2013: 18 · 2012: 4
- FWCI
- 9.44
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- Instituto de Salud Carlos III
- National Institute on Aging (P01AG011542, P01AG017586, AG17586, AG 11542, T32AG000255)
- National Institute of General Medical Sciences (T32GM007229, T32GM07229)
- 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
- GSK3α, GSK3β, Alzheimer's disease, amyloid plaques, neurofibrillary tangles, tau phosphorylation, tau misfolding, gene knockdown, memory impairment, therapeutic target
- MeSH terms
- Glycogen Synthase Kinase 3 beta, Alzheimer Disease, Animals, Brain, Disease Models, Animal, Female, Male, Memory Disorders, Mice, Inbred C57BL, Mice, Transgenic, Genetic Therapy, Signal Transduction, Neurofibrillary Tangles, tau Proteins, Glycogen Synthase Kinase 3, Mice, Gene Knockdown Techniques, Plaque, Amyloid
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