title: Sirtuin 2 Inhibition Improves Cognitive Performance and Acts on Amyloid-β Protein Precursor Processing in Two Alzheimer's Disease Mouse Models.
abstract: 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.
authors.affiliation: IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Department of Neuroscience, Milan, Italy.
authors.forename: Gloria
authors.initials: G
authors.lastname: Biella
authors.affiliation: IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Department of Neuroscience, Milan, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Fusco
authors.affiliation: IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Department of Neuroscience, Milan, Italy.
authors.forename: Emanuele
authors.initials: E
authors.lastname: Nardo
authors.affiliation: IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Department of Neuroscience, Milan, Italy.
authors.forename: Ottavia
authors.initials: O
authors.lastname: Bernocchi
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
authors.forename: Alessio
authors.initials: A
authors.lastname: Colombo
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.|Neuroproteomics, Klinikum rechts der Isar, and Institute for Advanced Study, Technische Universität München, Munich, Germany.|Munich Center for Systems Neurology (SyNergy), Munich, Germany.
authors.forename: Stefan F
authors.initials: SF
authors.lastname: Lichtenthaler
authors.affiliation: IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Department of Neuroscience, Milan, Italy.
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Forloni
authors.affiliation: IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Department of Neuroscience, Milan, Italy.
authors.forename: Diego
authors.initials: D
authors.lastname: Albani
mesh_terms: D000544:Alzheimer Disease / Q000150:complications* / Q000235:genetics / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001549:Benzamides / Q000494:pharmacology / Q000627:therapeutic use; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D003072:Cognition Disorders / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D005663:Furans / Q000494:pharmacology / Q000627:therapeutic use; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005910:Glioma / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011804:Quinolines / Q000494:pharmacology / Q000627:therapeutic use; D056565:Sirtuin 2 / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: C000603971:3-(1-azepanylsulfonyl)-N-(3-bromphenyl)benzamide; C521855:AGK2 compound; C491049:Aif1 protein, mouse; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D001549:Benzamides; D002135:Calcium-Binding Proteins; D004791:Enzyme Inhibitors; D005663:Furans; D005904:Glial Fibrillary Acidic Protein; D008840:Microfilament Proteins; D010446:Peptide Fragments; D011804:Quinolines; D013449:Sulfonamides; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D056565:Sirtuin 2
keywords: AK-7; Alzheimer’s disease; Sirtuin 2; amyloid-β protein precursor processing; tau