Phenylbutyrate rescues dendritic spine loss associated with memory deficits in a mouse model of Alzheimer disease
Abstract
Alzheimer's disease (AD) and ageing are associated with impaired learning and memory, and recent findings point toward modulating chromatin remodeling through histone acetylation as a promising therapeutic strategy. Here we report that systemic administration of the HDAC inhibitor 4-phenylbutyrate (PBA) reinstated fear learning in the Tg2576 mouse model of AD. Tg2576 mice develop age-dependent amyloid pathology and cognitive decline that closely mimics disease progression in humans. Memory reinstatement by PBA was observed independently of the disease stage: both in 6-month-old Tg2576 mice, at the onset of the first symptoms, but also in aged, 12- to 16-month-old mice, when amyloid plaque deposition and major synaptic loss has occurred. Reversal of learning deficits was associated to a PBA-induced clearance of intraneuronal Aβ accumulation, which was accompanied by mitigation of endoplasmic reticulum (ER) stress, and to restoration of dendritic spine densities of hippocampal CA1 pyramidal neurons to control levels. Furthermore, the expression of plasticity-related proteins such as the NMDA receptor subunit NR2B and the synaptic scaffold SAP102 was significantly increased by PBA. Our data suggest that the beneficial effects of PBA in memory are mediated both via its chemical chaperone-like activity and via the transcriptional activation of a cluster of proteins required for the induction of synaptic plasticity and structural remodeling.
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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 [23]
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- Authors
- Ricobaraza, A., Cuadrado‐Tejedor, M., Marco, S., Pérez‐Otaño, I., & García‐Osta, A.
- Affiliations
- Biomedical Research Networking Center on Neurodegenerative Diseases (ES)
- Centro de Investigación Médica Aplicada (ES)
- Corresponding author
- Pérez‐Otaño, Isabel
- García‐Osta, Ana
- Venue
- Hippocampus
- Publisher
- Wiley
- Published
- 2010-11-10
- Volume
- 22
- Issue
- 5
- Pages
- 1040-1050
- ISSN
- 1050-9631 (ISSN-L)
- 1098-1063
- OpenAlex
- W2080612159
- Cited by
- 239
- References
- 17
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 12 · 2023: 16 · 2022: 8 · 2021: 16 · 2020: 14 · 2019: 15 · 2018: 20 · 2017: 17 · 2016: 19 · 2015: 13 · 2014: 29 · 2013: 30 · 2012: 12
- FWCI
- 11.27
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Hippocampus (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Keywords
- 4-phenylbutyric acid, Alzheimer's disease, Tg2576 mice, histone deacetylase inhibitors, fear learning, memory impairment, dendritic spine loss, amyloid-beta clearance, endoplasmic reticulum stress, chemical chaperones, synaptic plasticity, NMDA receptor NR2B, SAP102, CA1 pyramidal neurons, chromatin remodeling, histone acetylation
- MeSH terms
- Age Factors, Alzheimer Disease, Animals, Disease Models, Animal, Fear, Humans, Membrane Proteins, Memory, Memory Disorders, Mice, Inbred C57BL, Mice, Transgenic, Synaptic Transmission, Phenylbutyrates, Receptors, N-Methyl-D-Aspartate, Amyloid beta-Peptides, Pyramidal Cells, Dendritic Spines, Mice, Guanylate Kinases, CA1 Region, Hippocampal, Histone Deacetylase Inhibitors, Plaque, Amyloid, Endoplasmic Reticulum Stress
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