RETRACTED: Inhibition of HDAC3 reverses Alzheimer’s disease-related pathologies in vitro and in the 3xTg-AD mouse model
Open accessAbstract
Alzheimer’s disease (AD) is the leading cause of age-related dementia. Neuropathological hallmarks of AD include brain deposition of β-amyloid (Aβ) plaques and accumulation of both hyperphosphorylated and acetylated tau. RGFP-966, a brain-penetrant and selective HDAC3 inhibitor, or HDAC3 silencing, increases BDNF expression, increases histone H3 and H4 acetylation, decreases tau phosphorylation and tau acetylation at disease-associated sites, reduces β-secretase cleavage of the amyloid precursor protein (APP), and decreases Aβ 1–42 accumulation in HEK-293 cells overexpressing APP with the double Swedish mutation (HEK/APP sw ). In the triple transgenic AD mouse model (3xTg-AD), repeated administration of 3 and 10 mg/kg of RGFP-966 reverses pathological tau phosphorylation at Thr 181 , Ser 202 , and Ser 396 , increases levels of the Aβ degrading enzyme Neprilysin in plasma, decreases Aβ 1–42 protein levels in the brain and periphery, and improves spatial learning and memory. Finally, we show that RGFP-966 decreases Aβ 1–42 accumulation and both tau acetylation and phosphorylation at disease residues in neurons derived from induced pluripotent stem cells obtained from APOEε4-carrying AD patients. These data indicate that HDAC3 plays an important regulatory role in the expression and regulation of proteins associated with AD pathophysiology, supporting the notion that HDAC3 may be a disease-modifying therapeutic target.
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RGFP-966, a selective HDAC3 silencing agent, reduces both Aβ protein load and hyperphosphorylated Tau.
“RGFP-966, a selective HDAC3 silencing agent, reduces not only the Aβ protein load but also hyperphosphorylated Tau [144]”
From Beneficial Effects of Spirulina Consumption on Brain Health (2022) · cites this paper as [144]
The effect of RGFP-966 suggests an effect of C-PC on Tau protein.
“suggesting an effect of C-PC on Tau protein.”
From Beneficial Effects of Spirulina Consumption on Brain Health (2022) · cites this paper as [144]
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- Authors
- Janczura, K. J., Volmar, C.-H., Sartor, G. C., Rao, S. J., Ricciardi, N. R., Lambert, G., Brothers, S. P., & Wahlestedt, C.
- Affiliations
- University of Miami (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2018-11-05
- Volume
- 115
- Issue
- 47
- Pages
- E11148-E11157
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC6255210
- OpenAlex
- W2900379577
- Cited by
- 183
- References
- 49
- Citations by year
- 2026: 3 · 2025: 15 · 2024: 30 · 2023: 35 · 2022: 24 · 2021: 25 · 2020: 36 · 2019: 13 · 2018: 2
- FWCI
- 13.06
- Type
- journal article
- Language
- en
- Status
- Retracted
- Update notices
- retraction (2024-08-21)
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- HHS | NIH | National Institute on Alcohol Abuse and Alcoholism (5R01AA023781)
- American Historical Association (17PRE33660831)
- HHS | NIH | National Institute of Neurological Disorders and Stroke (5R01NS092671)
- Florida Department of Health (5AZ09, 6AZ08)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- Alzheimer's disease, HDAC3 inhibition, histone deacetylase, tau phosphorylation, tau acetylation, amyloid-beta, 3xTg-AD mice, brain-derived neurotrophic factor, histone acetylation, neprilysin, iPSC-derived neurons, spatial learning and memory, disease-modifying therapy
- MeSH terms
- Histone Deacetylase 3, Acetylation, Acrylamides, Alzheimer Disease, Animals, Histone Deacetylases, Histones, Humans, Memory, Mice, Transgenic, Neurons, Phenylenediamines, Phosphorylation, Neprilysin, Amyloid beta-Peptides, tau Proteins, Brain-Derived Neurotrophic Factor, Gene Silencing, Mice, Histone Deacetylase Inhibitors, Induced Pluripotent Stem Cells, HEK293 Cells, Spatial Learning
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