Phenylbutyrate ameliorates cognitive deficit and reduces tau pathology in an Alzheimer's disease mouse model.
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.
Ricobaraza
Ana
A
Division of Neurosciences, CIMA, University of Navarra, Pamplona, CIBERNED, Spain.
Cuadrado-Tejedor
Mar
M
Pérez-Mediavilla
Alberto
A
Frechilla
Diana
D
Del Río
Joaquin
J
García-Osta
Ana
A
D000107:Acetylation / Q000187:drug effects; D000544:Alzheimer Disease / Q000150:complications* / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000704:Analysis of Variance; D000818:Animals; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation / Q000379:methods; D003072:Cognition Disorders / Q000188:drug therapy* / Q000209:etiology*; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D006624:Hippocampus / Q000473:pathology; D006657:Histones / Q000378:metabolism; D006801:Humans; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000187:drug effects; D010446:Peptide Fragments / Q000378:metabolism; D010654:Phenylbutyrates / Q000627:therapeutic use*; D024801:Tauopathies / Q000188:drug therapy* / Q000209:etiology*
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D006657:Histones; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; D010654:Phenylbutyrates; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); C075773:4-phenylbutyric acid