Ana García-Osta and Isabel Pérez-Otaño contributed equally to this work.
Phenylbutyrate rescues dendritic spine loss associated with memory deficits in a mouse model of Alzheimer disease
Version of Record online: 10 NOV 2010
Copyright © 2010 Wiley Periodicals, Inc.
Special Issue: Proteins and Proteomics
Volume 22, Issue 5, pages 1040–1050, May 2012
How to Cite
Ricobaraza, A., Cuadrado-Tejedor, M., Marco, S., Pérez-Otaño, I. and García-Osta, A. (2012), Phenylbutyrate rescues dendritic spine loss associated with memory deficits in a mouse model of Alzheimer disease. Hippocampus, 22: 1040–1050. doi: 10.1002/hipo.20883
- Issue online: 14 APR 2012
- Version of Record online: 10 NOV 2010
- Manuscript Accepted: 15 AUG 2010
- Spanish Ministry of Education and Science. Grant Number: CSD2008–00005
- Pyrinees Cooperation Program. Grant Number: CTP IIQ011701.RI1
- UTE project CIMA
- fear memory;
- histone acetylation;
- dendritic spine;
- endoplasmic reticulum stress
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. © 2010 Wiley Periodicals, Inc.