Diet supplementation by resveratrol reduces hippocampal amyloid and tau pathology in SAMP8 mice: participation of sirtuin 1 pathway

M. Pallàs, D. Porquet, S. Bayod, A. Camins, A.M. Canudas, J. del Valle. University of Barcelone, Pharmacology and Medical Chemistry, Spain

Resveratrol is a natural polyphenol found in red grape skin and red wine that has been reported to activate sirtuin 1 (SIRT1). This protein plays a key role in regulating different cellular processes through deacetylation p53, FOXO transcription factors, PGC-1α, NFκB and others. These and other reasons lead to a gain in the relevance of this molecule as a promising new therapeutic approach to treat several neurodegenerative diseases as Alzheimer’s disease. For example, SIRT1 loss has been found in patients with Alzheimer’s disease (AD) and this decrease is correlated with amyloid deposits Senescence-accelerated mice 8 (SAMP8) mice, a model of aging. SAMP8 have been proposed as a model of AD as this strain shows alterations in learning and memory, amyloid-β accumulation, tau hyperphosphorylation and increased oxidative stress. By using western blot and immunohistochemical analysis we studied the effect of resveratrol supplemented diet of on amyloid and tau pathology in hippocampus of SAMP8.

We have found that a resveratrol supplemented diet is able to prolong lifespan (p<0.001) and reduce AD-like pathology SAMP8. Levels of SIRT1 are also increased in SAMP8 brain, while levels of acetylated p53 are decreased in the same areas (p<0.05). Furthermore, resveratrol is able to reduce the cognitive impairment, measured by object recognition test (ORT)(p<0.01).

Here we presented the effects of resveratrol dietary supplementation on hallmarks of AD described in these animals. First we have demonstrated that the amyloid burden decreased, and also an increase in alpha-secretase (ADAM10)(p<0.01). These results indicated a beneficial effect of Resveratrol on amyloid pathology in SAMP8.

On the other hand, we found a decrease in tau phosphorylation in hippocampus (p<0.05), without modification of activity of tau kinases (GSK3beta, cdk5, JNK), that may explain the positive effect on ORT.

In conclusion the Sirtuin 1-activator resveratrol can act on ADAM-10 expression, amylodosis and tau phosphorylation in the hippocampus of a murine model of AD.

The experimental protocol was approved by the Ethics Committee of the Universitat de Barcelona and complied with ‘Principles of laboratory animal care’ and the European Communities Council Directive (86/609/EEC). Student’s t-test or ANOVA following Tukey\'s Multiple Comparison Test where performed when necessary

ACKNOWLEDGEMENTS: SAF-2009-13093, SAF2011-23631 from the “Ministerio de Educación y Ciencia”, and DPS2008-06998-C01,C02 from the “Instituto de Salud Carlos III”, 2009/SGR00893 from the “Generalitat de Catalunya” and 610RT0405 from the Programa Iberoamericano de Ciencia y Tecnologia para el Desarrollo (CYTED). Ayudas a la Investigación Fundación MAPFRE 2011.