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Phenylbutyrate ameliorates cognitive deficit and reduces tau pathology in an Alzheimer's disease mouse model.

Author	Ana Ricobaraza, Mar Cuadrado-Tejedor, Alberto Pérez-Mediavilla, Diana Frechilla, Joaquin Del Río, Ana García-Osta, Ana Ricobaraza, Mar Cuadrado-Tejedor, Alberto Pérez-Mediavilla, Diana Frechilla, Joaquin Del Río, Ana García-Osta, Ana Ricobaraza, Mar Cuadrado-Tejedor, Alberto Pérez-Mediavilla, Diana Frechilla, Joaquin Del Río, Ana García-Osta
Citation Information	Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 34:1721-32 (2009)
Keywords	Acetylation, Alzheimer Disease, Amyloid beta-Protein, Amyloid beta-Protein Precursor, Analysis of Variance, Animals, Cells, Cultured, Chromatin Immunoprecipitation, Cognition Disorders, Disease Models, Animal, Embryo, Mammalian, Hippocampus, Histones, Humans, Maze Learning, Mice, Mice, Transgenic, Nerve Tissue Proteins, Neurons, Peptide Fragments, Phenylbutyrates, Tauopathies
Related Products	06-866
Pub Med ID	19145227

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.