Inhibitors of Class 1 Histone Deacetylases Reverse Contextual Memory Deficits in a Mouse Model of Alzheimer's Disease
Open accessAbstract
Alzheimer's disease (AD) is a neurodegenerative disorder characterized clinically by cognitive impairments that progress to dementia and death. The earliest symptoms of AD present as a relatively pure deficit in memory retrieval. Therefore, drug treatments that intervene in the early stages of AD by rescuing memory deficits could be promising therapies to slow, or even reverse progression of the disease. In this study, we tested the potential of systemic histone deacetylase inhibitor (HDACi) treatment to rescue cognitive deficits in a mouse model of AD. APPswe/PS1dE9 mice showed pronounced contextual memory impairments beginning at 6 months of age. Chronic HDACi injections (2-3 weeks) did not alter contextual memory formation in normal mice, but had profound effects in transgenic animals. Injections of sodium valproate, sodium butyrate, or vorinostat (suberoylanilide hydroxamic acid; Zolinza) completely restored contextual memory in these mutant mice. Further behavioral testing of the HDACi-treated transgenic mice showed that the newly consolidated memories were stably maintained over a 2-week period. Measurement of the HDAC isoform selectivity profile of sodium valproate, sodium butyrate, and vorinostat revealed the common inhibition of class I HDACs (HDAC1, 2, 3, 8) with little effect on the class IIa HDAC family members (HDAC4, 5, 7, 9) and inhibition of HDAC6 only by vorinostat. These preclinical results indicate that targeted inhibition of class I HDAC isoforms is a promising avenue for treating the cognitive deficits associated with early stage AD.
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HDAC inhibitors restore memory deficits in mice.
“HDAC inhibitors restore memory deficits in mice,161”
From Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential (2023) · cites this paper as [161]
Small molecule inhibitors of class I HDACs can alleviate memory deficits in mouse AD models.
“small molecule inhibitors of class I HDACs can alleviate memory deficits in mouse AD models [9–11].”
From CI-994 is a dual modulator of class I HDACs and Wnt/β-catenin signaling for the treatment of Alzheimer's disease (2026) · cites this paper as [10]
Several recent studies reported that commercially available HDACIs alter Aβ levels by an unknown mechanism.
“Interestingly, several recent studies reported that the commercially available HDACIs alter Aβ levels by an unknown mechanism (Kilgore et al., 2010;Ricobaraza et al., 2011).”
From Mercaptoacetamide-based class II HDAC inhibitor lowers Aβ levels and improves learning and memory in a mouse model of Alzheimer's disease (2013) · cites this paper as Kilgore et al., 2010
The Results and Discussion report that HDAC inhibitors restored memory performance in APP/PS1 mice, while the Discussion mentions elevated Aβ in the context of Alzheimer’s pathology. Neither those passages nor searches for treatment-related changes in amyloid levels show that the inhibitors altered Aβ levels or discuss a mechanism for such a change. (LLM, conf=0.73)
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- Authors
- Kilgore, M., Miller, C. A., Fass, D. M., Hennig, K. M., Haggarty, S. J., Sweatt, J. D., & Rumbaugh, G.
- Affiliations
- University of Alabama at Birmingham (US)
- Broad Institute (US)
- Corresponding author
- Rumbaugh, Gavin
- Venue
- Neuropsychopharmacology
- Published
- 2009-12-09
- Volume
- 35
- Issue
- 4
- Pages
- 870-880
- ISSN
- 0893-133X (ISSN-L)
- 1740-634X
- PMC
- PMC3055373
- OpenAlex
- W2090054406
- Cited by
- 727
- References
- 8
- Citations by year
- 2026: 32 · 2025: 34 · 2024: 43 · 2023: 31 · 2022: 25 · 2021: 33 · 2020: 41 · 2019: 30 · 2018: 53 · 2017: 48 · 2016: 51 · 2015: 40 · 2014: 68 · 2013: 68 · 2012: 58
- FWCI
- 28.81
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Neuropsychopharmacology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Brain Research Foundation
- American Health Assistance Foundation
- McKnight Foundation
- Evelyn F. McKnight Brain Research Foundation
- Stanley Medical Research Institute
- National Alliance for Research on Schizophrenia and Depression
- National Institute of Mental Health
- National Institute on Drug Abuse (R01DA028301, R00DA024761)
- National Institute of Neurological Disorders and Stroke
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Keywords
- Alzheimer's disease, histone deacetylase inhibitors, class I HDACs, contextual memory, memory consolidation, APP/PS1 mice, valproic acid, sodium butyrate, vorinostat, HDAC isoform selectivity, cognitive impairment
- MeSH terms
- Alzheimer Disease, Analysis of Variance, Animals, Conditioning, Classical, Disease Models, Animal, Enzyme Inhibitors, Fear, Female, Hippocampus, Humans, Male, Memory Disorders, Mice, Inbred C57BL, Mice, Transgenic, Amyloid beta-Protein Precursor, Mice, Presenilin-1, Histone Deacetylase 1, In Vitro Techniques
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