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

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.

Automated summary

Alzheimer's disease predominantly affects women and is characterized by metabolic deregulation and synaptic failure. In a study on female APPswe/PS1dE9 mice, a model for early AD, it was found that these mice exhibited learning and memory deficits, increased anxiety-like behavior, and signs of fear generalization. The prefrontal cortex showed decreased long-term potentiation and reduced levels of sirtuin-1 and sestrin-2, while synaptic markers remained unchanged. However, activation of sirtuin-1 did not restore abnormal cortical plasticity in APP/PS1 female mice; instead, its inhibition increased plasticity. These findings suggest that mood and memory dysfunction in early AD may be associated with a decrease in synaptic plasticity and sirtuin-1 levels in the prefrontal cortex.