SIRT1 Overexpression in Mouse Hippocampus Induces Cognitive Enhancement Through Proteostatic and Neurotrophic Mechanisms

Rubén Corpas, Susana Revilla, Suzanna Ursulet, Marco Castro-Freire, Perla Kaliman, Valérie Petegnief, Lydia Giménez-Llort, Chamsy Sarkis, Mercè Pallàs, Coral Sanfeliu

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42 Citations (Scopus)

Abstract

© 2016, Springer Science+Business Media New York. SIRT1 induces cell survival and has shown neuroprotection against amyloid and tau pathologies in Alzheimer’s disease (AD). However, protective effects against memory loss or the enhancement of cognitive functions have not yet been proven. We aimed to investigate the benefits induced by SIRT1 overexpression in the hippocampus of the AD mouse model 3xTg-AD and in control non-transgenic mice. A lentiviral vector encoding mouse SIRT1 or GFP, selectively transducing neurons, was injected into the dorsal CA1 hippocampal area of 4-month-old mice. Six-month overexpression of SIRT1 fully preserved learning and memory in 10-month-old 3xTg-AD mice. Remarkably, SIRT1 also induced cognitive enhancement in healthy non-transgenic mice. Neuron cultures of 3xTg-AD mice, which show traits of AD-like pathology, and neuron cultures from non-transgenic mice were also transduced with lentiviral vectors to analyze beneficial SIRT1 mechanisms. We uncovered novel pathways of SIRT1 neuroprotection through enhancement of cell proteostatic mechanisms and activation of neurotrophic factors not previously reported such as GDNF, present in both AD-like and healthy neurons. Therefore, SIRT1 may increase neuron function and resilience against AD.
Original languageEnglish
Pages (from-to)5604-5619
JournalMolecular Neurobiology
Volume54
Issue number7
DOIs
Publication statusPublished - 1 Sep 2017

Keywords

  • 3xTg-AD mice
  • Cognitive enhancement
  • Glial cell line-derived neurotrophic factor (GDNF)
  • Insulin-degrading enzyme (IDE)
  • Proteasome
  • SIRT1

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