Neuroprotective Sirtuin ratio reversed by ApoE4
Open accessAbstract
Significance: This manuscript links ApoE4-mediated signaling with Sirtuin function. Specifically, we show that ApoE4, but not ApoE3, reduces neuroprotective SirT1 levels. Our data support the hypothesis that neuronal connectivity, as reflected in the ratios of critical mediators such as sAPPα:Aβ, SirT1:SirT2, APP:p-APP, and Tau:p-Tau, is programmatically altered by ApoE4. Thus ApoE4, SirT1/2, p-Tau, and p-APP, all may be part of a signaling network that is affected in AD, providing a model for therapeutic candidate screening in AD drug discovery. These findings offer a unique insight into the mechanism by which ApoE4 confers risk for the development of Alzheimer’s disease.
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Forced expression of ApoE4 reduced mRNA and protein levels of Sirt1, an enzyme that mediates NAD+-dependent deacetylation of PGC-1α, thus enhancing its transcriptional activity.
“Theendakara et al. (2013) reported that forced expression of ApoE4 reduced mRNA and protein levels of sirtuin 1 (Sirt1), an enzyme that mediates NAD ϩ -dependent deacetylation of PGC-1␣, thus enhancing its transcriptional activity (Canto ´and Auwerx, 2009).”
From Human ApoE Isoforms Differentially Modulate Brain Glucose and Ketone Body Metabolism: Implications for Alzheimer's Disease Risk Reduction and Early Intervention (2018) · cites this paper as Theendakara et al. (2013)
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- Authors
- Theendakara, V., Patent, A., Peters Libeu, C. A., Philpot, B., Flores, S., Descamps, O., Poksay, K. S., Zhang, Q., Cailing, G., Hart, M., John, V., Rao, R. V., & Bredesen, D. E.
- Affiliations
- Buck Institute for Research on Aging (US)
- The Buck Institute for Research on Aging, Novato, CA 94945;
- The University of Texas at San Antonio Health Science Center (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2013-10-21
- Volume
- 110
- Issue
- 45
- Pages
- 18303-18308
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3831497
- OpenAlex
- W2138992810
- Cited by
- 101
- References
- 2
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 4 · 2023: 5 · 2022: 5 · 2021: 14 · 2020: 7 · 2019: 13 · 2018: 7 · 2017: 13 · 2016: 10 · 2015: 12 · 2014: 5
- FWCI
- 6.25
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- University of California, San Francisco
- National Institute on Aging (AG034427-02, R01AG034427)
- School of Medicine, University of California, San Francisco
- 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
- Alzheimer's disease, APOE ε4, amyloid precursor protein, amyloid-beta, sAPPα, SIRT1, SIRT2, tau phosphorylation, APP phosphorylation, programmed cell death, neuroprotection, drug candidates
- MeSH terms
- Alzheimer Disease, Analysis of Variance, Gene Expression Regulation, Humans, Phosphorylation, Blotting, Western, Amyloid beta-Protein Precursor, tau Proteins, Surface Plasmon Resonance, Sirtuins, Immunoprecipitation, Apolipoprotein E3, Apolipoprotein E4, Drug Discovery, Real-Time Polymerase Chain Reaction
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