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

被引:110
作者
Corpas, Ruben [1 ]
Revilla, Susana [1 ]
Ursulet, Suzanna [2 ]
Castro-Freire, Marco [3 ]
Kaliman, Perla [1 ]
Petegnief, Valerie [1 ]
Gimenez-Llort, Lydia [4 ]
Sarkis, Chamsy [2 ]
Pallas, Merce [5 ,6 ]
Sanfeliu, Coral [1 ,3 ]
机构
[1] IIBB CSIC, C Rossello 161,6th Floor, Barcelona 08036, Spain
[2] NewVectys, F-91140 Villebon Sur Yvette, France
[3] Inst Invest Biomed August Pi & Sunyer IDIBAPS, Barcelona 08036, Spain
[4] Univ Autonoma Barcelona, Dept Psychiat & Forens Med, Bellaterra 08193, Spain
[5] Univ Barcelona, Fac Farm, Inst Neurociencies, E-08028 Barcelona, Spain
[6] CIBERNED, Barcelona 08028, Spain
关键词
SIRT1; 3xTg-AD mice; Cognitive enhancement; Proteasome; Insulin-degrading enzyme (IDE); Glial cell line-derived neurotrophic factor (GDNF); INTRACELLULAR A-BETA; IN-VITRO MODEL; ALZHEIMERS-DISEASE; EPIGENETIC REGULATION; CALORIE RESTRICTION; AMYLOID HYPOTHESIS; UP-REGULATION; TAU; PROTEIN; MICE;
D O I
10.1007/s12035-016-0087-9
中图分类号
Q189 [神经科学];
学科分类号
071006 [神经生物学];
摘要
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.
引用
收藏
页码:5604 / 5619
页数:16
相关论文
共 91 条
[1]
Localization and Trafficking of Amyloid-β Protein Precursor and Secretases: Impact on Alzheimer's Disease [J].
Agostinho, Paula ;
Pliassova, Anna ;
Oliveira, Catarina R. ;
Cunha, Rodrigo A. .
JOURNAL OF ALZHEIMERS DISEASE, 2015, 45 (02) :329-347
[2]
Translocation of PKC by Yessotoxin in an in Vitro Model of Alzheimer's Disease with Improvement of Tau and β-Amyloid Pathology [J].
Alonso, Eva ;
Vale, Carmen ;
Vieytes, Mercedes R. ;
Botana, Luis M. .
ACS CHEMICAL NEUROSCIENCE, 2013, 4 (07) :1062-1070
[3]
13-Desmethyl spirolide-C is neuroprotective and reduces intracellular Aβ and hyperphosphorylated tau in vitro [J].
Alonso, Eva ;
Vale, Carmen ;
Vieytes, Mercedes R. ;
Laferla, Frank M. ;
Gimenez-Llort, Lydia ;
Botana, Luis M. .
NEUROCHEMISTRY INTERNATIONAL, 2011, 59 (07) :1056-1065
[4]
The Cholinergic Antagonist Gymnodimine Improves Aβ and Tau Neuropathology in an in Vitro Model of Alzheimer Disease [J].
Alonso, Eva ;
Vale, Carmen ;
Vieytes, Mercedes R. ;
Laferla, Frank M. ;
Gimenez-Llort, Lydia ;
Botana, Luis M. .
CELLULAR PHYSIOLOGY AND BIOCHEMISTRY, 2011, 27 (06) :783-794
[5]
Alzheimer's Disease International (ADI), 2015, WORLD ALZHEIMER REPO
[6]
Sirtuin-dependent epigenetic regulation in the maintenance of genome integrity [J].
Bosch-Presegue, Laia ;
Vaquero, Alejandro .
FEBS JOURNAL, 2015, 282 (09) :1745-1767
[7]
Object recognition memory and the rodent hippocampus [J].
Broadbent, Nicola J. ;
Gaskin, Stephane ;
Squire, Larry R. ;
Clark, Robert E. .
LEARNING & MEMORY, 2010, 17 (01) :794-800
[8]
SIRT1 and Neural Cell Fate Determination [J].
Cai, Yulong ;
Xu, Le ;
Xu, Haiwei ;
Fan, Xiaotang .
MOLECULAR NEUROBIOLOGY, 2016, 53 (05) :2815-2825
[9]
Overexpression of growth-associated proteins in the neurons of adult transgenic mice [J].
Caroni, P .
JOURNAL OF NEUROSCIENCE METHODS, 1997, 71 (01) :3-9
[10]
5-Lipoxygenase gene transfer worsens memory, amyloid, and tau brain pathologies in a mouse model of alzheimer disease [J].
Chu, Jin ;
Giannopoulos, Phillip F. ;
Ceballos-Diaz, Carolina ;
Golde, Todd E. ;
Pratico, Domenico .
ANNALS OF NEUROLOGY, 2012, 72 (03) :442-454