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Ana Garcia Osta"Rescue of memory and dendritic spine loss in an AD mouse model using phenylbutyrate"

Abstract :

Epigenetic mechanisms play a particularly important role in the regulation of transcription gene in response to environmental factors, drugs of abuse and cognitive processes.
Recent studies have suggested that inhibitors of histone deacetylation (HDAC's) can be a useful therapy for restore cognitive function in aging-related dementias. Such drugs modulate gene expression, affect neuron survival and plasticity as well as being neuroprotective in some models of neurodegeneration. 
Sodium phenylbutyrate (PBA) is an orphan drug indicated the urea cycle disorders, an inherited metabolic disease. Besides being an inhibitor of histone deacetylases (HDAC), PBA acts as a chemical chaperone and can potentially inhibit the formation of protein aggregates such as those found in neurons of Alzheimer´s disease (AD) patients. 
We have identified PBA as an effective cognitive-enhancer in the Tg2576 transgenic mouse model of AD, which overexpresses a mutant form of the amyloid precursor protein (APP). Additionally, PBA reversed the pathological hallmarks of the disease in this animal model, including a decrease in tau phosphorylation, a clearance of intraneuronal Aβ and a restoration of the dendritic spine density of hippocampal CA1 pyramidal neurons. (Ricobaraza et al. 2009, 2012). Kubota et al. (2006) demonstrated that PBA could operate independently of its iHDAC activity as a chemical chaperone that helps in cell proteostatic events. In fact, Tg2576 neuronal cultures treated with PBA decreased the production of Aβ42 in the conditioned medium, whereas this effect was not observed with other HDAC inhibitor. Our results support the potential of appropriate multimodal drugs in the management of AD symptoms and of AD-related neurodegeneration.

Selected publications

Tadalafil crosses the blood-brain barrier and reverses cognitive dysfunction in a mouse model of AD.García-Barroso C, Ricobaraza A, Pascual-Lucas M, Unceta N, Rico AJ, Goicolea MA, Sallés J, Lanciego JL, Oyarzabal J, Franco R, Cuadrado-Tejedor M, García-Osta A.
Neuropharmacology. 2012 Jul 7. [Epub ahead of print]
Defining the mechanism of action of 4-phenylbutyrate to develop a small-molecule-based therapy for Alzheimer's disease.Cuadrado-Tejedor M, García-Osta A, Ricobaraza A, Oyarzabal J, Franco R.Curr Med Chem. 2011;18(36):5545-53. Review.

Chronic mild stress accelerates the onset and progression of the Alzheimer's disease phenotype in Tg2576 mice.Cuadrado-Tejedor M, Ricobaraza A, Frechilla D, Franco R, Pérez-Mediavilla A, Garcia-Osta A.J Alzheimers Dis. 2012;28(3):567-78.

Sildenafil restores cognitive function without affecting β-amyloid burden in a mouse model of Alzheimer's disease.Cuadrado-Tejedor M, Hervias I, Ricobaraza A, Puerta E, Pérez-Roldán JM, García-Barroso C, Franco R, Aguirre N, García-Osta A.Br J Pharmacol. 2011 Dec;164(8):2029-41. doi: 10.1111/j.1476-5381.2011.01517.x.

Christophe Mulle de l'IINS