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SIRT2 Inhibition Rescues Neurodegenerative Pathology but Increases Systemic Inflammation in a Transgenic Mouse Model of Alzheimer’s Disease

Sirtuin 2 (SIRT2) has been proposed to have a central role on aging, inflammation, cancer and neurodegenerative diseases; however, its specific function remains controversial. Recent studies propose SIRT2 pharmacological inhibition as a therapeutic strategy for several neurodegenerative diseases inc...

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Autores principales: Sola-Sevilla, Noemi, Mesa-Lombardo, Alberto, Aleixo, Mikel, Expósito, Sara, Diaz-Perdigón, Teresa, Azqueta, Amaya, Zamani, Farzad, Suzuki, Takayoshi, Maioli, Silvia, Eroli, Francesca, Matton, Anna, Ramírez, Maria J., Solas, Maite, Tordera, Rosa M., Martín, Eduardo D., Puerta, Elena
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer US 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10577113/
https://www.ncbi.nlm.nih.gov/pubmed/37698780
http://dx.doi.org/10.1007/s11481-023-10084-9
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author Sola-Sevilla, Noemi
Mesa-Lombardo, Alberto
Aleixo, Mikel
Expósito, Sara
Diaz-Perdigón, Teresa
Azqueta, Amaya
Zamani, Farzad
Suzuki, Takayoshi
Maioli, Silvia
Eroli, Francesca
Matton, Anna
Ramírez, Maria J.
Solas, Maite
Tordera, Rosa M.
Martín, Eduardo D.
Puerta, Elena
author_facet Sola-Sevilla, Noemi
Mesa-Lombardo, Alberto
Aleixo, Mikel
Expósito, Sara
Diaz-Perdigón, Teresa
Azqueta, Amaya
Zamani, Farzad
Suzuki, Takayoshi
Maioli, Silvia
Eroli, Francesca
Matton, Anna
Ramírez, Maria J.
Solas, Maite
Tordera, Rosa M.
Martín, Eduardo D.
Puerta, Elena
author_sort Sola-Sevilla, Noemi
collection PubMed
description Sirtuin 2 (SIRT2) has been proposed to have a central role on aging, inflammation, cancer and neurodegenerative diseases; however, its specific function remains controversial. Recent studies propose SIRT2 pharmacological inhibition as a therapeutic strategy for several neurodegenerative diseases including Alzheimer’s disease (AD). Surprisingly, none of these published studies regarding the potential interest of SIRT2 inhibition has assessed the peripheral adverse side consequences of this treatment. In this study, we demonstrate that the specific SIRT2 inhibitor, the compound 33i, does not exhibit genotoxic or mutagenic properties. Moreover, pharmacological treatment with 33i, improved cognitive dysfunction and long-term potentiation, reducing amyloid pathology and neuroinflammation in the APP/PS1 AD mouse model. However, this treatment increased peripheral levels of the inflammatory cytokines IL-1β, TNF, IL-6 and MCP-1. Accordingly, peripheral SIRT2 inhibition with the blood brain barrier impermeable compound AGK-2, worsened the cognitive capacities and increased systemic inflammation. The analysis of human samples revealed that SIRT2 is increased in the brain but not in the serum of AD patients. These results suggest that, although SIRT2 pharmacological inhibition may have beneficial consequences in neurodegenerative diseases, its pharmacological inhibition at the periphery would not be recommended and the systemic adverse side effects should be considered. This information is essential to maximize the therapeutic potential of SIRT2 inhibition not only for AD but also for other neurodegenerative diseases. GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11481-023-10084-9.
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spelling pubmed-105771132023-10-17 SIRT2 Inhibition Rescues Neurodegenerative Pathology but Increases Systemic Inflammation in a Transgenic Mouse Model of Alzheimer’s Disease Sola-Sevilla, Noemi Mesa-Lombardo, Alberto Aleixo, Mikel Expósito, Sara Diaz-Perdigón, Teresa Azqueta, Amaya Zamani, Farzad Suzuki, Takayoshi Maioli, Silvia Eroli, Francesca Matton, Anna Ramírez, Maria J. Solas, Maite Tordera, Rosa M. Martín, Eduardo D. Puerta, Elena J Neuroimmune Pharmacol Research Sirtuin 2 (SIRT2) has been proposed to have a central role on aging, inflammation, cancer and neurodegenerative diseases; however, its specific function remains controversial. Recent studies propose SIRT2 pharmacological inhibition as a therapeutic strategy for several neurodegenerative diseases including Alzheimer’s disease (AD). Surprisingly, none of these published studies regarding the potential interest of SIRT2 inhibition has assessed the peripheral adverse side consequences of this treatment. In this study, we demonstrate that the specific SIRT2 inhibitor, the compound 33i, does not exhibit genotoxic or mutagenic properties. Moreover, pharmacological treatment with 33i, improved cognitive dysfunction and long-term potentiation, reducing amyloid pathology and neuroinflammation in the APP/PS1 AD mouse model. However, this treatment increased peripheral levels of the inflammatory cytokines IL-1β, TNF, IL-6 and MCP-1. Accordingly, peripheral SIRT2 inhibition with the blood brain barrier impermeable compound AGK-2, worsened the cognitive capacities and increased systemic inflammation. The analysis of human samples revealed that SIRT2 is increased in the brain but not in the serum of AD patients. These results suggest that, although SIRT2 pharmacological inhibition may have beneficial consequences in neurodegenerative diseases, its pharmacological inhibition at the periphery would not be recommended and the systemic adverse side effects should be considered. This information is essential to maximize the therapeutic potential of SIRT2 inhibition not only for AD but also for other neurodegenerative diseases. GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11481-023-10084-9. Springer US 2023-09-12 2023 /pmc/articles/PMC10577113/ /pubmed/37698780 http://dx.doi.org/10.1007/s11481-023-10084-9 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research
Sola-Sevilla, Noemi
Mesa-Lombardo, Alberto
Aleixo, Mikel
Expósito, Sara
Diaz-Perdigón, Teresa
Azqueta, Amaya
Zamani, Farzad
Suzuki, Takayoshi
Maioli, Silvia
Eroli, Francesca
Matton, Anna
Ramírez, Maria J.
Solas, Maite
Tordera, Rosa M.
Martín, Eduardo D.
Puerta, Elena
SIRT2 Inhibition Rescues Neurodegenerative Pathology but Increases Systemic Inflammation in a Transgenic Mouse Model of Alzheimer’s Disease
title SIRT2 Inhibition Rescues Neurodegenerative Pathology but Increases Systemic Inflammation in a Transgenic Mouse Model of Alzheimer’s Disease
title_full SIRT2 Inhibition Rescues Neurodegenerative Pathology but Increases Systemic Inflammation in a Transgenic Mouse Model of Alzheimer’s Disease
title_fullStr SIRT2 Inhibition Rescues Neurodegenerative Pathology but Increases Systemic Inflammation in a Transgenic Mouse Model of Alzheimer’s Disease
title_full_unstemmed SIRT2 Inhibition Rescues Neurodegenerative Pathology but Increases Systemic Inflammation in a Transgenic Mouse Model of Alzheimer’s Disease
title_short SIRT2 Inhibition Rescues Neurodegenerative Pathology but Increases Systemic Inflammation in a Transgenic Mouse Model of Alzheimer’s Disease
title_sort sirt2 inhibition rescues neurodegenerative pathology but increases systemic inflammation in a transgenic mouse model of alzheimer’s disease
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10577113/
https://www.ncbi.nlm.nih.gov/pubmed/37698780
http://dx.doi.org/10.1007/s11481-023-10084-9
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