AMYLOID BETA SEX-SPECIFICALLY ALTERS SYNAPTIC TRANSMISSION

Abstract

Nearly 2/3 of Alzheimer's disease (AD) patients are women and studies suggest they have a faster disease progression. Despite this clinical profile, only a small fraction of research includes animals of both sexes and even fewer carefully examine data for potential sex differences. Our research focuses on how amyloid beta (Aβ), a pathological agent in AD, induces changes in neuronal Ca2+ signaling and causes synaptic dysfunction in the hippocampus. It is known that alternations in Ca2+ homoeostasis precede Aβ deposits and cognitive decline in AD patients and behavioural deficits in mouse models. However, little progress has been made to elucidate the mechanisms that underlie the sex-specific disease progression in AD. The purpose of our investigation was to characterize how Aβ sex-specifically alters hippocampal synaptic transmission. We used the well-characterized Aβ25–35 infusion AD model, as this paradigm recapitulates the process of sporadic AD. Aβ25–35 was infused, i.c.v., into brains of adult male and ovariectomized female mice and experiments were conducted 2 weeks later. A dot blot confirmed that Aβ25–35 infused animals had increased Aβ1–42 in their brains. Using whole-cell patch-clamp recording in conjunction with Ca2+ imaging of CA1 pyramidal neurons, we examined Aβ-induced changes to synaptic transmission. We found that female mice infused with Aβ25–35 had an increased post-burst afterhyperpolarization (AHP), a paradigm used as a proxy for changes in Ca2+ homeostasis. They also had an increased facilitation in response to trains of stimuli. Interestingly, Aβ-infused male mice did not show these changes. Instead, Aβ-infused male mice had alterations in their AMPA/NMDA ratio, which was not found in female mice. Our data suggest that the mechanistic action of Aβ differs between male and female mice. Understanding how Aβ impacts synaptic function and Ca2+ homeostasis within the male and female hippocampus differently could explain the faster disease progression in females and lead to sex-specific therapeutic intervention. We highlight the need to consider sex differences in AD pathophysiology and therapeutic interventions.