Downregulation of Sirtuin 1 Does Not Account for the Impaired Long-Term Potentiation in the Prefrontal Cortex of Female APPswe/PS1dE9 Mice Modelling Alzheimer’s Disease
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Published:2023-04-09
Issue:8
Volume:24
Page:6968
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ISSN:1422-0067
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Container-title:International Journal of Molecular Sciences
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language:en
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Short-container-title:IJMS
Author:
Lopes Cátia R.1, Silva Joana S.1, Santos Joana1, Rodrigues Matilde S.1ORCID, Madeira Daniela1, Oliveira Andreia1, Moreira-de-Sá Ana1, Lourenço Vanessa S.1ORCID, Gonçalves Francisco Q.1, Silva Henrique B.1ORCID, Simões Ana Patrícia1, Rolo Anabela P.12, Canas Paula M.1, Tomé Ângelo R.12ORCID, Palmeira Carlos M.12ORCID, Lopes João Pedro1ORCID, Cunha Rodrigo A.13, Agostinho Paula13, Ferreira Samira G.1ORCID
Affiliation:
1. CNC—Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal 2. Department of Life Sciences, Faculty of Sciences and Technology, University of Coimbra, 3004-531 Coimbra, Portugal 3. Faculty of Medicine, University of Coimbra, 3004-504 Coimbra, Portugal
Abstract
Alzheimer’s disease (AD), which predominantly affects women, involves at its onset a metabolic deregulation associated with a synaptic failure. Here, we performed a behavioral, neurophysiological and neurochemical characterization of 9-month-old female APPswe/PS1dE9 (APP/PS1) mice as a model of early AD. These animals showed learning and memory deficits in the Morris water maze, increased thigmotaxis and anxiety-like behavior and showed signs of fear generalization. Long-term potentiation (LTP) was decreased in the prefrontal cortex (PFC), but not in the CA1 hippocampus or amygdala. This was associated with a decreased density of sirtuin-1 in cerebrocortical synaptosomes and a decreased density of sirtuin-1 and sestrin-2 in total cerebrocortical extracts, without alterations of sirtuin-3 levels or of synaptic markers (syntaxin, synaptophysin, SNAP25, PSD95). However, activation of sirtuin-1 did not affect or recover PFC-LTP deficit in APP/PS1 female mice; instead, inhibition of sirtuin-1 increased PFC-LTP magnitude. It is concluded that mood and memory dysfunction in 9-month-old female APP/PS1 mice is associated with a parallel decrease in synaptic plasticity and in synaptic sirtuin-1 levels in the prefrontal cortex, although sirtiun1 activation failed to restore abnormal cortical plasticity.
Funder
Centro 2020 La Caixa Foundation FCT
Subject
Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis
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