Phenylbutyrate ameliorates cognitive deficit and reduces tau pathology in an Alzheimer's disease mouse model
Abstract
Chromatin modification through histone acetylation is a molecular pathway involved in the regulation of transcription underlying memory storage. Sodium 4-phenylbutyrate (4-PBA) is a well-known histone deacetylase inhibitor, which increases gene transcription of a number of genes, and also exerts neuroprotective effects. In this study, we report that administration of 4-PBA reversed spatial learning and memory deficits in an established mouse model of Alzheimer's disease (AD) without altering beta-amyloid burden. We also observed that the phosphorylated form of tau was decreased in the AD mouse brain after 4-PBA treatment, an effect probably due to an increase in the inactive form of the glycogen synthase kinase 3beta (GSK3beta). Interestingly, we found a dramatic decrease in brain histone acetylation in the transgenic mice that may reflect an indirect transcriptional repression underlying memory impairment. The administration of 4-PBA restored brain histone acetylation levels and, as a most likely consequence, activated the transcription of synaptic plasticity markers such as the GluR1 subunit of the AMPA receptor, PSD95, and microtubule-associated protein-2. The results suggest that 4-PBA, a drug already approved for clinical use, may provide a novel approach for the treatment of AD.
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Benzamide compound 1 has a significantly different binding mode, in which the thiophene group is inserted into the foot pocket.
“The benzamide compound 1 has a significantly different binding mode, in which the thiophene group is inserted into the 'foot pocket' (Fig. 3 B ) (20-23, 32, 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 [22]
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- Authors
- Ricobaraza, A., Cuadrado-Tejedor, M., Pérez-Mediavilla, A., Frechilla, D., Del Río, J., & García-Osta, A.
- Affiliations
- Centro de Investigación Médica Aplicada (ES)
- ORCID
- Ricobaraza, Ana
- Venue
- Neuropsychopharmacology
- Published
- 2009-01-14
- Volume
- 34
- Issue
- 7
- Pages
- 1721-1732
- ISSN
- 0893-133X (ISSN-L)
- 1740-634X
- OpenAlex
- W2051075231
- Cited by
- 423
- References
- 9
- Citations by year
- 2026: 20 · 2025: 22 · 2024: 25 · 2023: 18 · 2022: 20 · 2021: 18 · 2020: 22 · 2019: 15 · 2018: 13 · 2017: 25 · 2016: 24 · 2015: 31 · 2014: 37 · 2013: 47 · 2012: 27
- FWCI
- 19.06
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Neuropsychopharmacology (publishedVersion)
- PubMed (publishedVersion)
- Deposito Adademico Digital Universidad De Navarra (University of Navarra) (submittedVersion)
- Funders
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
- Keywords
- 4-phenylbutyric acid, Alzheimer's disease, histone deacetylase inhibitors, histone acetylation, tau phosphorylation, glycogen synthase kinase-3β, spatial learning and memory deficits, cognitive impairment, synaptic plasticity, GluR1, PSD-95, MAP2, amyloid-beta, neuroprotection
- MeSH terms
- Acetylation, Alzheimer Disease, Analysis of Variance, Animals, Cells, Cultured, Cognition Disorders, Disease Models, Animal, Embryo, Mammalian, Hippocampus, Histones, Humans, Mice, Transgenic, Nerve Tissue Proteins, Neurons, Peptide Fragments, Phenylbutyrates, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Maze Learning, Tauopathies, Chromatin Immunoprecipitation, Mice
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