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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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Published in: | Journal of neuroimmune pharmacology 2023-09, Vol.18 (3), p.529-550 |
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creator | 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 |
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.
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doi_str_mv | 10.1007/s11481-023-10084-9 |
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Graphical Abstract</description><identifier>ISSN: 1557-1890</identifier><identifier>ISSN: 1557-1904</identifier><identifier>EISSN: 1557-1904</identifier><identifier>DOI: 10.1007/s11481-023-10084-9</identifier><identifier>PMID: 37698780</identifier><language>eng</language><publisher>New York: Springer US</publisher><subject>Biomedical and Life Sciences ; Biomedicine ; Cell Biology ; Immunology ; Inflammation ; Medicin och hälsovetenskap ; Neurosciences ; Pharmacology/Toxicology ; Virology</subject><ispartof>Journal of neuroimmune pharmacology, 2023-09, Vol.18 (3), p.529-550</ispartof><rights>The Author(s) 2023</rights><rights>The Author(s) 2023. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c590t-beb6a742223abfc0041328c16f7b17d0e86faf528a12b4feb27064af5fdf66c53</citedby><cites>FETCH-LOGICAL-c590t-beb6a742223abfc0041328c16f7b17d0e86faf528a12b4feb27064af5fdf66c53</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,27924,27925</link.rule.ids><backlink>$$Uhttp://kipublications.ki.se/Default.aspx?queryparsed=id:153655719$$DView record from Swedish Publication Index$$Hfree_for_read</backlink><backlink>$$Uhttp://kipublications.ki.se/Default.aspx?queryparsed=id:237698780$$DView record from Swedish Publication Index$$Hfree_for_read</backlink></links><search><creatorcontrib>Sola-Sevilla, Noemi</creatorcontrib><creatorcontrib>Mesa-Lombardo, Alberto</creatorcontrib><creatorcontrib>Aleixo, Mikel</creatorcontrib><creatorcontrib>Expósito, Sara</creatorcontrib><creatorcontrib>Diaz-Perdigón, Teresa</creatorcontrib><creatorcontrib>Azqueta, Amaya</creatorcontrib><creatorcontrib>Zamani, Farzad</creatorcontrib><creatorcontrib>Suzuki, Takayoshi</creatorcontrib><creatorcontrib>Maioli, Silvia</creatorcontrib><creatorcontrib>Eroli, Francesca</creatorcontrib><creatorcontrib>Matton, Anna</creatorcontrib><creatorcontrib>Ramírez, Maria J.</creatorcontrib><creatorcontrib>Solas, Maite</creatorcontrib><creatorcontrib>Tordera, Rosa M.</creatorcontrib><creatorcontrib>Martín, Eduardo D.</creatorcontrib><creatorcontrib>Puerta, Elena</creatorcontrib><title>SIRT2 Inhibition Rescues Neurodegenerative Pathology but Increases Systemic Inflammation in a Transgenic Mouse Model of Alzheimer’s Disease</title><title>Journal of neuroimmune pharmacology</title><addtitle>J Neuroimmune Pharmacol</addtitle><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.
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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.
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subjects | Biomedical and Life Sciences Biomedicine Cell Biology Immunology Inflammation Medicin och hälsovetenskap Neurosciences Pharmacology/Toxicology Virology |
title | SIRT2 Inhibition Rescues Neurodegenerative Pathology but Increases Systemic Inflammation in a Transgenic Mouse Model of Alzheimer’s Disease |
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