TY - JOUR
T1 - Sirtuin 2 Inhibition Improves Cognitive Performance and Acts on Amyloid-β Protein Precursor Processing in Two Alzheimer's Disease Mouse Models
AU - Biella, Gloria
AU - Fusco, Federica
AU - Nardo, Emanuele
AU - Bernocchi, Ottavia
AU - Colombo, Alessio
AU - Lichtenthaler, Stefan F.
AU - Forloni, Gianluigi
AU - Albani, Diego
PY - 2016
Y1 - 2016
N2 - The neuropathological hallmarks of Alzheimer's disease (AD) are extracellular plaques built up by the accumulation of the amyloid-β protein precursor (AβPP)-derived peptide β (Aβ), and intracellular tangles of hyperphosphorylated tau protein. Sirtuin 2 (SIRT2) is a member of the sirtuin family, featuring conserved enzymes with deacetylase activity and involved in several cell molecular pathways. We investigated the importance of SIRT2 inhibition in AD. We inhibited SIRT2 by small molecules (AGK-2, AK-7) and examined AβPP metabolism in H4-SW neuroglioma cells overexpressing AβPP and two AD transgenic mouse models (3xTg-AD and APP23). The in vitro studies suggested that the inhibition of SIRT2 reduced Aβ production; in vivo data showed an improvement of cognitive performance in the novel object recognition test, and an effect on AβPP proteolytic processing leading to a reduction of soluble β-AβPP and an increase of soluble α-AβPP protein. In 3xTg-AD mice, we noticed that total tau protein level rose. Overall, our pre-clinical data support a role for SIRT2 inhibition in the improvement of cognitive performance and the modulation of molecular mechanisms relevant for AD, thus deserving attention as possible therapeutic strategy.
AB - The neuropathological hallmarks of Alzheimer's disease (AD) are extracellular plaques built up by the accumulation of the amyloid-β protein precursor (AβPP)-derived peptide β (Aβ), and intracellular tangles of hyperphosphorylated tau protein. Sirtuin 2 (SIRT2) is a member of the sirtuin family, featuring conserved enzymes with deacetylase activity and involved in several cell molecular pathways. We investigated the importance of SIRT2 inhibition in AD. We inhibited SIRT2 by small molecules (AGK-2, AK-7) and examined AβPP metabolism in H4-SW neuroglioma cells overexpressing AβPP and two AD transgenic mouse models (3xTg-AD and APP23). The in vitro studies suggested that the inhibition of SIRT2 reduced Aβ production; in vivo data showed an improvement of cognitive performance in the novel object recognition test, and an effect on AβPP proteolytic processing leading to a reduction of soluble β-AβPP and an increase of soluble α-AβPP protein. In 3xTg-AD mice, we noticed that total tau protein level rose. Overall, our pre-clinical data support a role for SIRT2 inhibition in the improvement of cognitive performance and the modulation of molecular mechanisms relevant for AD, thus deserving attention as possible therapeutic strategy.
KW - AK-7
KW - Alzheimer's disease
KW - amyloid-β protein precursor processing
KW - Sirtuin 2
KW - tau
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UR - http://www.scopus.com/inward/citedby.url?scp=84981350310&partnerID=8YFLogxK
U2 - 10.3233/JAD-151135
DO - 10.3233/JAD-151135
M3 - Article
AN - SCOPUS:84981350310
VL - 53
SP - 1193
EP - 1207
JO - Journal of Alzheimer's Disease
JF - Journal of Alzheimer's Disease
SN - 1387-2877
IS - 3
ER -