Resveratrol induces resilience against age-related neurodegeneration through improvement of proteostasis

Trabajo presentado en el IUBMB Focused Meeting on «Molecular aspects of aging and longevity», celebrado en Atenas, del 16 al 19 de octubre de 2017Resveratrol is a natural compound that mimics the antiaging effect of caloric restriction, which is mainly mediated through SIRT1, a NAD+-dependent deacetylase that induces longevity and neuroprotection by regulating the acetylation homeostasis of key proteins. Resveratrol is a potential preventive agent against age-related neurodegeneration and was proven to protect against Alzheimer’s disease (AD)-like pathology in experimental models. In this study, we aimed to analyze the effects of resveratrol on the brain status of control non-transgenic (NoTg) mice and AD transgenic mice to discern the mechanisms involved in a potential inducement of resilience against age-related neurodegeneration and AD. NoTg and 3xTg-AD mice were fed with a diet supplemented with trans-resveratrol, at 100 mg/kg during 10 month. The period of 2 to 12 months of age covered a broad period of the AD pathology progression, from the pre-symptomatic to the advanced AD pathology phase. Resveratrol administration induced complete protection against memory loss and brain pathology in 3xTg-AD mice, and also induced cognitive enhancement in NoTg mice. Resveratrol reduced the presence of Aβ and p-tau pathology in the hippocampus of 3xTg-AD mouse. Proteostasis analysis showed in both healthy and AD mice: (i) increased levels of the amyloid degrading enzyme Neprilysin; (ii) increase of protein proteasome levels and activity; (iii) reduction of the amyloidogenic secretase BACE1. Resveratrol increased the AMPK protein levels, then upregulating SIRT1 pathway as shown by activation of PGC-1α and CREB in 3xTg-AD and NoTg mice, resulting in further beneficial changes in the mitochondrial function and plasticity processes, respectively. Our data demonstrate that resveratrol induces cognitive enhancement and neuroprotection against amyloid and tau pathologies. Improvement of proteostasis by resveratrol, in both healthy and AD mice, suggests it is a mechanism of brain resilience and defense against neurodegeneration caused by accumulation of aberrant proteins.Supported by SAF2016-77703, MINECO and ERDF.Peer reviewe