SIRT1 Overexpression in Mouse Hippocampus Induces Cognitive Enhancement Through Proteostatic and Neurotrophic Mechanisms.
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.
Institut d'Investigacions Biomèdiques de Barcelona (IIBB) - CSIC, C/Rosselló 161, 6th floor, 08036, Barcelona, Spain.
Rubén
R
Corpas
Institut d'Investigacions Biomèdiques de Barcelona (IIBB) - CSIC, C/Rosselló 161, 6th floor, 08036, Barcelona, Spain.
Susana
S
Revilla
NewVectys, 91140, Villebon-sur-Yvette, France.
Suzanna
S
Ursulet
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036, Barcelona, Spain.
Marco
M
Castro-Freire
Institut d'Investigacions Biomèdiques de Barcelona (IIBB) - CSIC, C/Rosselló 161, 6th floor, 08036, Barcelona, Spain.
Perla
P
Kaliman
Institut d'Investigacions Biomèdiques de Barcelona (IIBB) - CSIC, C/Rosselló 161, 6th floor, 08036, Barcelona, Spain.
Valérie
V
Petegnief
Department of Psychiatry and Forensic Medicine, Universitat Autònoma de Barcelona, 08193, Bellaterra, Spain.
Lydia
L
Giménez-Llort
NewVectys, 91140, Villebon-sur-Yvette, France.
Chamsy
C
Sarkis
Facultat de Farmàcia, Institut de Neurociències, Universitat de Barcelona and CIBERNED, 08028, Barcelona, Spain.
Mercè
M
Pallàs
Institut d'Investigacions Biomèdiques de Barcelona (IIBB) - CSIC, C/Rosselló 161, 6th floor, 08036, Barcelona, Spain. coral.sanfeliu@iibb.csic.es.|Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036, Barcelona, Spain. coral.sanfeliu@iibb.csic.es.
Coral
http://orcid.org/0000-0002-9004-1206
C
Sanfeliu
D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D003071:Cognition / Q000502:physiology*; D004195:Disease Models, Animal; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D007858:Learning / Q000502:physiology*; D008297:Male; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism; D018697:Nootropic Agents / Q000378:metabolism; D056564:Sirtuin 1 / Q000378:metabolism*
D016564:Amyloid beta-Protein Precursor; D018697:Nootropic Agents; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1
3xTg-AD mice; Cognitive enhancement; Glial cell line-derived neurotrophic factor (GDNF); Insulin-degrading enzyme (IDE); Proteasome; SIRT1