An epigenetic blockade of cognitive functions in the neurodegenerating brain
Open accessAbstract
Cognitive decline is a debilitating feature of most neurodegenerative diseases of the central nervous system, including Alzheimer's disease. The causes leading to such impairment are only poorly understood and effective treatments are slow to emerge. Here we show that cognitive capacities in the neurodegenerating brain are constrained by an epigenetic blockade of gene transcription that is potentially reversible. This blockade is mediated by histone deacetylase 2, which is increased by Alzheimer's-disease-related neurotoxic insults in vitro, in two mouse models of neurodegeneration and in patients with Alzheimer's disease. Histone deacetylase 2 associates with and reduces the histone acetylation of genes important for learning and memory, which show a concomitant decrease in expression. Importantly, reversing the build-up of histone deacetylase 2 by short-hairpin-RNA-mediated knockdown unlocks the repression of these genes, reinstates structural and synaptic plasticity, and abolishes neurodegeneration-associated memory impairments. These findings advocate for the development of selective inhibitors of histone deacetylase 2 and suggest that cognitive capacities following neurodegeneration are not entirely lost, but merely impaired by this epigenetic blockade.
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Viral-mediated knockdown of HDAC2 can restore structural and synaptic plasticity, improving memory loss associated with neurodegeneration.
“viral-mediated knockdown of HDAC2 can restore both structural and synaptic plasticity, ultimately leading to an improvement in memory loss associated with neurodegeneration.135”
From Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential (2023) · cites this paper as [135]
The HDAC2-inhibitor structures revealed an overall HDAC2 protein conformation similar to a previously solved HDAC2 structure, albeit at significantly higher resolution.
“The structures revealed an overall HDAC2 protein conformation similar to a previously solved HDAC2 structure, albeit at significantly higher resolution (Table 1 and Fig. 2) (17-19, 31, 33).”
From Histone Deacetylase (HDAC) Inhibitor Kinetic Rate Constants Correlate with Cellular Histone Acetylation but Not Transcription and Cell Viability (2013) · cites this paper as [17]
Our copy discusses HDAC2 abundance in neurodegenerating brain tissue (Abstract) and HDAC2 knockdown (Methods, Experimental manipulations). Searches for HDAC2-inhibitor structures, crystal structures, and resolution found no passage comparing protein conformations or structural resolution. (LLM, conf=0.75)
Experimental — accuracy not yet measuredIncreased levels of HDAC2 and HDAC6 are detected in AD mouse models and AD patients.
“In addition, increased levels of HDAC2 and HDAC6 were detected in AD mouse models and AD patients.296,297”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [296]
Expression of HDAC2 increases with aging in AD mouse models and patients.
“Expression of HDAC2 increases with aging in AD mouse models and patients [508].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [508]
HDAC2 overexpression reduces dendritic spine density and impairs synaptic plasticity and memory by blocking expression of genes related to neuroplasticity, whereas downregulation or inhibition of HDACs restores synaptic and cognitive function in AD animal models.
“HDAC2 overexpression reduces dendritic spine density, and impairs synaptic plasticity and memory by blocking expression of genes related to neuroplasticity, whereas downregulation or inhibition of HDACs has been proven successful in restoring synaptic and cognitive function in AD animal models [508, 509].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [508]
Viral-mediated knockdown of Hdac2 restores synaptic plasticity deficits, enhances synapse number, and improves behavioral abnormalities in a mouse model of neurological disease.
“Supporting this notion, viral-mediated knockdown of Hdac2 restores synaptic plasticity deficits, enhances synapse number, and improves behavioral abnormalities in a mouse model of neurological disease.”
From Epigenetic mechanisms of major depression: Targeting neuronal plasticity (2018) · cites this paper as [53]
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References 39 · Cited by 853
- Authors
- Gräff, J., Rei, D., Guan, J.-S., Wang, W.-Y., Seo, J., Hennig, K. M., Nieland, T. J. F., Fass, D. M., Kao, P. F., Kahn, M., Su, S. C., Samiei, A., Joseph, N., Haggarty, S. J., Delalle, I., & Tsai, L.-H.
- Affiliations
- Massachusetts Institute of Technology (US)
- Howard Hughes Medical Institute (US)
- Broad Institute (US)
- Boston University (US)
- Corresponding author
- Tsai, Li-Huei
- ORCID
- Venue
- Nature
- Published
- 2012-02-29
- Volume
- 483
- Issue
- 7388
- Pages
- 222-226
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3498952
- OpenAlex
- W2142388403
- Cited by
- 853
- References
- 39
- Citations by year
- 2026: 40 · 2025: 53 · 2024: 54 · 2023: 53 · 2022: 58 · 2021: 42 · 2020: 69 · 2019: 44 · 2018: 72 · 2017: 52 · 2016: 58 · 2015: 72 · 2014: 88 · 2013: 66 · 2012: 32
- FWCI
- 55.51
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
- Funders
- Howard Hughes Medical Institute
- National Institute of Mental Health (R01MH095088)
- National Institute on Drug Abuse (R01DA028301)
- National Institute of Neurological Disorders and Stroke (R01NS078839)
- 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
- HDAC2, Alzheimer's disease, neurodegeneration, cognitive decline, memory impairment, epigenetic gene repression, histone acetylation, synaptic plasticity, neuroplasticity, HDAC2 inhibitors, shRNA knockdown
- MeSH terms
- Acetylation, Alzheimer Disease, Animals, Brain, Disease Models, Animal, Gene Expression Regulation, Hippocampus, Histones, Humans, Hydrogen Peroxide, Memory Disorders, Neuronal Plasticity, Peptide Fragments, Phosphorylation, Promoter Regions, Genetic, Receptors, Glucocorticoid, RNA Polymerase II, Amyloid beta-Peptides, Neurodegenerative Diseases, Epigenesis, Genetic, Mice, Gene Knockdown Techniques, Histone Deacetylase 2
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