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Resveratrol Induces Brain Resilience Against Alzheimer Neurodegeneration Through Proteostasis Enhancement

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Abstract

Resveratrol is a natural compound that mimics the antioxidant and antiaging effects of caloric restriction, mainly mediated through SIRT1, a deacetylase that induces longevity and neuroprotection. We aimed to analyze the effects of resveratrol on the brain status of control non-transgenic (NoTg) and AD transgenic (3xTg-AD) mice to discern the mechanisms involved in a potential inducement of resilience against age-related neurodegeneration and Alzheimer’s disease (AD). Mice were fed with a diet supplemented with 100 mg/kg of resveratrol from 2 months of age during 10 months. Resveratrol administration induced complete protection against memory loss and brain pathology in 3xTg-AD mice, and also induced cognitive enhancement in healthy NoTg mice. Resveratrol improved exploration and reduced anxiety in both mouse strains, indicative of well-being. Resveratrol reduced the presence of Aβ and p-tau pathology in the hippocampus of the 3xTg-AD mouse. Proteostasis analysis showed the following in both NoTg and 3xTg-AD mice: (i) increased levels of the amyloid-degrading enzyme neprilysin, (ii) reduction of the amyloidogenic secretase BACE1, and (iii) increase of proteasome protein levels and enhancement of proteasome activity. Resveratrol also increased AMPK protein levels, then upregulating the SIRT1 pathway, as shown by the activation of PGC-1α and CREB in both mice, resulting in further beneficial changes. Our data demonstrated that resveratrol induces cognitive enhancement and neuroprotection against amyloid and tau pathologies. Improvement of proteostasis by resveratrol, in both healthy and AD mice, suggests that it is a mechanism of brain resilience and defense against neurodegeneration caused by the accumulation of aberrant proteins.

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Acknowledgements

We acknowledge the use of mice derived from the colony established by Dr. Lydia Giménez-Llort at the Universitat Autònoma de Barcelona with progenitors provided by Dr. Frank M LaFerla, University of California Irvine.

Funding

This study was supported by grants SAF2016-77703 and SAF2016-81716-REDC from Spanish MINECO and European Development Fund; 2017-SGR-106 from AGAUR and the CERCA Programme/Generalitat de Catalunya.

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Authors and Affiliations

  1. Institut d’Investigacions Biomèdiques de Barcelona (IIBB), CSIC and IDIBAPS, Barcelona, Spain

    Rubén Corpas, Eduard Rodríguez-Farré & Coral Sanfeliu

  2. CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain

    Rubén Corpas, Eduard Rodríguez-Farré & Coral Sanfeliu

  3. Faculty of Pharmacy and Food Sciences, Institut de Neurociències, Universitat de Barcelona and CIBERNED, Barcelona, Spain

    Christian Griñán-Ferré & Mercè Pallàs

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  1. Rubén Corpas
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  2. Christian Griñán-Ferré
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  3. Eduard Rodríguez-Farré
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  4. Mercè Pallàs
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  5. Coral Sanfeliu
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Correspondence to Rubén Corpas or Coral Sanfeliu.

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Animal handling and experimental procedures were approved by the Ethics Committee for animal experimentation (CEEA) of the University of Barcelona (UB) (Ref: DAAM 6523, CEEA), in accordance with the Decree 214/1997 of the Generalitat of Catalonia and the Directive 2010/63/EU of the European Union for animal experiments.

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The authors declare that they have no conflict of interest.

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Corpas, R., Griñán-Ferré, C., Rodríguez-Farré, E. et al. Resveratrol Induces Brain Resilience Against Alzheimer Neurodegeneration Through Proteostasis Enhancement. Mol Neurobiol 56, 1502–1516 (2019). https://doi.org/10.1007/s12035-018-1157-y

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