Estudio de la acción terapéutica del 4-fenilbutirato sódico sobre las funciones congnitivas de un modelo murino de enfermedad de alzheimermecanismos de acción

Resumen

Aberrations in protein folding, processing, and/or degradation are common features of Alzheimer's disease (AD), implying a role of quality control systems, such as molecular chaperones and the ubiquitin-proteasome pathway. 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. 4-PBA acts as a chemical chaperone reducing the load of mutant or unfolded proteins retained in the ER during cellular stress. In this study we report that administration of 4-PBA during 5 weeks (200 mg/kg, i.p.) reversed spatial learning and memory deficits in an established mouse model of AD (Tg2576, 15-16 month old) without altering β-amyloid (Aβ) burden. The phosphorylated form of tau was decreased in the AD mouse brain after treatment, an effect probably due to an increase in the active form of Akt which negatively regulates the glycogen synthase kinase 3ß (GSK3ß). 4-PBA was found to attenuate the increase in the phosphorylation of eukaryotic translation initiation factor-2 alpha (eIF2) and the decrease in the ER chaperone, glucose-regulated protein (GRP78) observed in the transgenic mice brain. We found also a dramatic decrease in brain histone acetylation in the transgenic mice, which can reflect an indirect transcriptional repression underlying memory impairment. The administration of 4-PBA increased brain histone acetylation and, therefore, activated the transcription of plasticity proteins, AMPA receptor GluR1 subunit and post synaptic density protein 95 (PSD95). The results suggest that these multiple actions of 4-PBA may provide a novel approach for the treatment of AD. Moreover, we performed another treatment using 6 month old Tg2576 mice, which were administered daily with PBA (200 mg/kg, i.p.) for 6 months. Chronic treatment prevented spatial learning and memory impairments of mice in the Morris water maze reversal phase. This effect was not associated with a decrease in the number of amyloid plaques in the brains of Tg2576. However, using the sandwich ELISA analysis, a significant decrease was detected in Aβ(1-42) levels in the frontal cortex of mice treated with PBA compared to the saline group. Using immunohistochemistry analysis we observed that this result is related to a decrease in the intracellular accumulation of Aβ. This accumulation was associated with abnormal synaptic morphology, before β-amyloid plaque pathology, suggesting that intracellular accumulation of Aβ plays a crucial role in Alzheimer¿s disease. We also found that chronic PBA treatment prevented the reductions of proteins of synaptic function and synaptic structure, including AMPA receptors subunits GluR1 and Glur2/3, PSD95 and c-fos. These results demonstrated that long-term PBA administration may prevent spatial learning and memory decline of Tg2576 mice by decreasing intraneuronal Aβ(1-42) and up-regulating synaptic plasticity related proteins in the hippocampus.