¹Division of Neurosciences, CIMA, University of Navarra, Pamplona, CIBERNED, Spain

Correspondence: Dr A García-Osta, Division of Neurosciences, CIMA, University of Navarra, Av. Pio XII 55, Pamplona, CIBERNED 31008, Spain. Tel: +011 34 948 19 47 00 2011; Fax: 011 34 948 19 47 15; E-mail: agosta@unav.es

Received 18 August 2008; Revised 14 November 2008; Accepted 2 December 2008; Published online 14 January 2009.

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 -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 3 (GSK3). 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.