Unravelling the role of SIRT2 in Alzheimer’s disease

Sirtuin 2 (SIRT2) has been proposed to have a central role on ageing, inflammation, and age-related pathologies such as AD. Recent studies propose the pharmacological inhibition of SIRT2 as a therapeutic strategy for several neurodegenerative diseases; nevertheless, its specific role is not well und...

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Detalhes bibliográficos
Autor: Sola-Sevilla, N. (Noemí)|||/items/22c978b4-5358-45c5-91be-8931900ae891
Formato: tesis doctoral
Fecha de publicación:2023
País:España
Recursos:Universidad de Navarra
Repositorio:Dadun. Depósito Académico Digital de la Universidad de Navarra
Idioma:inglés
OAI Identifier:oai:dadun.unav.edu:10171/67869
Acesso em linha:https://hdl.handle.net/10171/67869
Access Level:acceso abierto
Palavra-chave:Materias Investigacion::Farmacia::Farmacia y farmacología
SIRT2
Sirtuin 2
Alzheimer’s disease
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spelling Unravelling the role of SIRT2 in Alzheimer’s diseaseSola-Sevilla, N. (Noemí)|||/items/22c978b4-5358-45c5-91be-8931900ae891Materias Investigacion::Farmacia::Farmacia y farmacologíaSIRT2Sirtuin 2Alzheimer’s diseaseSirtuin 2 (SIRT2) has been proposed to have a central role on ageing, inflammation, and age-related pathologies such as AD. Recent studies propose the pharmacological inhibition of SIRT2 as a therapeutic strategy for several neurodegenerative diseases; nevertheless, its specific role is not well understood which varies depending on the organs, cell types and contexts analyzed. In attempt to understand the role of SIRT2 in ageing, the specific isoform 3 of SIRT2 (SIRT2.3) was overexpressed in mice hippocampus. Although, SIRT2.3 overexpression was not enough to accelerate ageing in a model with normal pattern of ageing, it promoted neuroinflammation and worsened age-related cognitive decline in the SAMP8 strain with an accelerated ageing phenotype. In this context, we postulated that its pharmacological inhibition could be a pharmacological strategy for the treatment of AD. Indeed, SIRT2 inhibition improved learning and memory deficits and reduced amyloid pathology and neuroinflammation; however, it increased peripheral inflammation. These peripheral deleterious effects were confirmed when the blood-brain barrier-impermeable SIRT2 inhibitor AGK-2 was administered. In this scenario where a beneficial effect of central SIRT2 inhibition while a deleterious peripheral effect was observed, we hypothesized that the specific deletion of SIRT2 in microglial cells could be the best therapeutic strategy to minimize the possible adverse effects. Upon an acute inflammatory insult, microglial SIRT2 deficiency reduced the inflammatory response. However, microglial SIRT2 seems to be essential in a chronic inflammatory context, such as AD, since its deletion increased mortality, worsened cognition, and impaired amyloid pathology in APP PS1 mouse model. These results highlight the relevance of further investigate the specific functions of SIRT2 in each cell type which is essential to maximize its potential as pharmacological target not only for AD but also for other neurodegenerative diseases.Universidad de NavarraPuerta, E. (Elena)Solas-Zubiaurre, M. (Maite)Dadun. Depósito Académico Digital Universidad de Navarra20232023-11-1620232023-11-1620232023-11-1620232023-10-30doctoral thesishttp://purl.org/coar/resource_type/c_db06info:eu-repo/semantics/doctoralThesisapplication/pdfhttps://hdl.handle.net/10171/67869reponame:Dadun. Depósito Académico Digital de la Universidad de Navarrainstname:Universidad de NavarraInglésengopen accesshttp://purl.org/coar/access_right/c_abf2info:eu-repo/semantics/openAccessoai:dadun.unav.edu:10171/678692026-06-21T12:47:57Z
dc.title.none.fl_str_mv Unravelling the role of SIRT2 in Alzheimer’s disease
title Unravelling the role of SIRT2 in Alzheimer’s disease
spellingShingle Unravelling the role of SIRT2 in Alzheimer’s disease
Sola-Sevilla, N. (Noemí)|||/items/22c978b4-5358-45c5-91be-8931900ae891
Materias Investigacion::Farmacia::Farmacia y farmacología
SIRT2
Sirtuin 2
Alzheimer’s disease
title_short Unravelling the role of SIRT2 in Alzheimer’s disease
title_full Unravelling the role of SIRT2 in Alzheimer’s disease
title_fullStr Unravelling the role of SIRT2 in Alzheimer’s disease
title_full_unstemmed Unravelling the role of SIRT2 in Alzheimer’s disease
title_sort Unravelling the role of SIRT2 in Alzheimer’s disease
dc.creator.none.fl_str_mv Sola-Sevilla, N. (Noemí)|||/items/22c978b4-5358-45c5-91be-8931900ae891
author Sola-Sevilla, N. (Noemí)|||/items/22c978b4-5358-45c5-91be-8931900ae891
author_facet Sola-Sevilla, N. (Noemí)|||/items/22c978b4-5358-45c5-91be-8931900ae891
author_role author
dc.contributor.none.fl_str_mv Puerta, E. (Elena)
Solas-Zubiaurre, M. (Maite)
Dadun. Depósito Académico Digital Universidad de Navarra
dc.subject.none.fl_str_mv Materias Investigacion::Farmacia::Farmacia y farmacología
SIRT2
Sirtuin 2
Alzheimer’s disease
topic Materias Investigacion::Farmacia::Farmacia y farmacología
SIRT2
Sirtuin 2
Alzheimer’s disease
description Sirtuin 2 (SIRT2) has been proposed to have a central role on ageing, inflammation, and age-related pathologies such as AD. Recent studies propose the pharmacological inhibition of SIRT2 as a therapeutic strategy for several neurodegenerative diseases; nevertheless, its specific role is not well understood which varies depending on the organs, cell types and contexts analyzed. In attempt to understand the role of SIRT2 in ageing, the specific isoform 3 of SIRT2 (SIRT2.3) was overexpressed in mice hippocampus. Although, SIRT2.3 overexpression was not enough to accelerate ageing in a model with normal pattern of ageing, it promoted neuroinflammation and worsened age-related cognitive decline in the SAMP8 strain with an accelerated ageing phenotype. In this context, we postulated that its pharmacological inhibition could be a pharmacological strategy for the treatment of AD. Indeed, SIRT2 inhibition improved learning and memory deficits and reduced amyloid pathology and neuroinflammation; however, it increased peripheral inflammation. These peripheral deleterious effects were confirmed when the blood-brain barrier-impermeable SIRT2 inhibitor AGK-2 was administered. In this scenario where a beneficial effect of central SIRT2 inhibition while a deleterious peripheral effect was observed, we hypothesized that the specific deletion of SIRT2 in microglial cells could be the best therapeutic strategy to minimize the possible adverse effects. Upon an acute inflammatory insult, microglial SIRT2 deficiency reduced the inflammatory response. However, microglial SIRT2 seems to be essential in a chronic inflammatory context, such as AD, since its deletion increased mortality, worsened cognition, and impaired amyloid pathology in APP PS1 mouse model. These results highlight the relevance of further investigate the specific functions of SIRT2 in each cell type which is essential to maximize its potential as pharmacological target not only for AD but also for other neurodegenerative diseases.
publishDate 2023
dc.date.none.fl_str_mv 2023
2023-11-16
2023
2023-11-16
2023
2023-11-16
2023
2023-10-30
dc.type.none.fl_str_mv doctoral thesis
http://purl.org/coar/resource_type/c_db06
dc.type.openaire.fl_str_mv info:eu-repo/semantics/doctoralThesis
format doctoralThesis
dc.identifier.none.fl_str_mv https://hdl.handle.net/10171/67869
url https://hdl.handle.net/10171/67869
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Universidad de Navarra
publisher.none.fl_str_mv Universidad de Navarra
dc.source.none.fl_str_mv reponame:Dadun. Depósito Académico Digital de la Universidad de Navarra
instname:Universidad de Navarra
instname_str Universidad de Navarra
reponame_str Dadun. Depósito Académico Digital de la Universidad de Navarra
collection Dadun. Depósito Académico Digital de la Universidad de Navarra
repository.name.fl_str_mv
repository.mail.fl_str_mv
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