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

  • Int J Mol Sci. 2023 Apr 9;24(8):6968. doi: 10.3390/ijms24086968.
Cátia R Lopes  1 ,  Joana S Silva  1 ,  Joana Santos  1 ,  Matilde S Rodrigues  1 ,  Daniela Madeira  1 ,  Andreia Oliveira  1 ,  Ana Moreira-de-Sá  1 ,  Vanessa S Lourenço  1 ,  Francisco Q Gonçalves  1 ,  Henrique B Silva  1 ,  Ana Patrícia Simões  1 ,  Anabela P Rolo  1  2 ,  Paula M Canas  1 ,  Ângelo R Tomé  1  2 ,  Carlos M Palmeira  1  2 ,  João Pedro Lopes  1 ,  Rodrigo A Cunha  1  3 ,  Paula Agostinho  1  3 ,  Samira G Ferreira  1
Affiliations
  • 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.
PMID: 37108131 DOI: 10.3390/ijms24086968
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.

Keywords
APP/PS1 mice; Alzheimer’s disease; LTP; memory; prefrontal cortex; sirtuins; synapse.
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