TY  - JOUR
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
TI  - Sirtuin 2 Inhibition Improves Cognitive Performance and Acts on Amyloid-β Protein Precursor Processing in Two Alzheimer's Disease Mouse Models.
JO  - Journal of Alzheimer's disease
VL  - 53
IS  - 3
SN  - 1387-2877
CY  - Amsterdam
PB  - IOS Press
M1  - DZNE-2020-05075
SP  - 1193-1207
PY  - 2016
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  - Alzheimer Disease: complications
KW  - Alzheimer Disease: genetics
KW  - Alzheimer Disease: pathology
KW  - Amyloid beta-Peptides: metabolism
KW  - Amyloid beta-Protein Precursor: genetics
KW  - Amyloid beta-Protein Precursor: metabolism
KW  - Animals
KW  - Benzamides: pharmacology
KW  - Benzamides: therapeutic use
KW  - Brain: drug effects
KW  - Brain: metabolism
KW  - Calcium-Binding Proteins: metabolism
KW  - Cell Line, Tumor
KW  - Cognition Disorders: drug therapy
KW  - Cognition Disorders: etiology
KW  - Cognition Disorders: metabolism
KW  - Cognition Disorders: pathology
KW  - Disease Models, Animal
KW  - Enzyme Inhibitors: pharmacology
KW  - Enzyme Inhibitors: therapeutic use
KW  - Furans: pharmacology
KW  - Furans: therapeutic use
KW  - Gene Expression Regulation: drug effects
KW  - Gene Expression Regulation: genetics
KW  - Glial Fibrillary Acidic Protein: metabolism
KW  - Glioma: pathology
KW  - Mice
KW  - Mice, Inbred C57BL
KW  - Mice, Transgenic
KW  - Microfilament Proteins: metabolism
KW  - Peptide Fragments: metabolism
KW  - Phosphorylation: drug effects
KW  - Quinolines: pharmacology
KW  - Quinolines: therapeutic use
KW  - Sirtuin 2: metabolism
KW  - Sulfonamides: pharmacology
KW  - Sulfonamides: therapeutic use
KW  - 3-(1-azepanylsulfonyl)-N-(3-bromphenyl)benzamide (NLM Chemicals)
KW  - AGK2 compound (NLM Chemicals)
KW  - Aif1 protein, mouse (NLM Chemicals)
KW  - Amyloid beta-Peptides (NLM Chemicals)
KW  - Amyloid beta-Protein Precursor (NLM Chemicals)
KW  - Benzamides (NLM Chemicals)
KW  - Calcium-Binding Proteins (NLM Chemicals)
KW  - Enzyme Inhibitors (NLM Chemicals)
KW  - Furans (NLM Chemicals)
KW  - Glial Fibrillary Acidic Protein (NLM Chemicals)
KW  - Microfilament Proteins (NLM Chemicals)
KW  - Peptide Fragments (NLM Chemicals)
KW  - Quinolines (NLM Chemicals)
KW  - Sulfonamides (NLM Chemicals)
KW  - amyloid beta-protein (1-40) (NLM Chemicals)
KW  - amyloid beta-protein (1-42) (NLM Chemicals)
KW  - Sirtuin 2 (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:27372638
DO  - DOI:10.3233/JAD-151135
UR  - https://pub.dzne.de/record/138753
ER  -