TY - JOUR
T1 - SIRT1 Overexpression in Mouse Hippocampus Induces Cognitive Enhancement Through Proteostatic and Neurotrophic Mechanisms
AU - Corpas, Rubén
AU - Revilla, Susana
AU - Ursulet, Suzanna
AU - Castro-Freire, Marco
AU - Kaliman, Perla
AU - Petegnief, Valérie
AU - Giménez-Llort, Lydia
AU - Sarkis, Chamsy
AU - Pallàs, Mercè
AU - Sanfeliu, Coral
PY - 2017/9/1
Y1 - 2017/9/1
N2 - © 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.
AB - © 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.
KW - 3xTg-AD mice
KW - Cognitive enhancement
KW - Glial cell line-derived neurotrophic factor (GDNF)
KW - Insulin-degrading enzyme (IDE)
KW - Proteasome
KW - SIRT1
U2 - 10.1007/s12035-016-0087-9
DO - 10.1007/s12035-016-0087-9
M3 - Article
SN - 0893-7648
VL - 54
SP - 5604
EP - 5619
JO - Molecular Neurobiology
JF - Molecular Neurobiology
IS - 7
ER -