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.
Keywords:
AK-7; Alzheimer’s disease; Sirtuin 2; amyloid-β protein precursor processing; tau.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Alzheimer Disease / complications*
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Alzheimer Disease / genetics
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Alzheimer Disease / pathology
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Amyloid beta-Peptides / metabolism
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Amyloid beta-Protein Precursor / genetics
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Amyloid beta-Protein Precursor / metabolism*
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Animals
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Benzamides / pharmacology
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Benzamides / therapeutic use
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Brain / drug effects
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Brain / metabolism
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Calcium-Binding Proteins / metabolism
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Cell Line, Tumor
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Cognition Disorders / drug therapy
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Cognition Disorders / etiology*
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Cognition Disorders / metabolism*
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Cognition Disorders / pathology
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Disease Models, Animal
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Enzyme Inhibitors / pharmacology
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Enzyme Inhibitors / therapeutic use
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Furans / pharmacology
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Furans / therapeutic use
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Gene Expression Regulation / drug effects
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Gene Expression Regulation / genetics
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Glial Fibrillary Acidic Protein / metabolism
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Glioma / pathology
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Microfilament Proteins / metabolism
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Peptide Fragments / metabolism
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Phosphorylation / drug effects
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Quinolines / pharmacology
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Quinolines / therapeutic use
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Sirtuin 2 / metabolism*
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Sulfonamides / pharmacology
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Sulfonamides / therapeutic use
Substances
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3-(1-azepanylsulfonyl)-N-(3-bromphenyl)benzamide
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AGK2 compound
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Aif1 protein, mouse
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Amyloid beta-Peptides
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Amyloid beta-Protein Precursor
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Benzamides
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Calcium-Binding Proteins
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Enzyme Inhibitors
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Furans
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Glial Fibrillary Acidic Protein
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Microfilament Proteins
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Peptide Fragments
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Quinolines
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Sulfonamides
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amyloid beta-protein (1-40)
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amyloid beta-protein (1-42)
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Sirtuin 2