Sex-Dependent Synaptic Alterations in a Mouse Model of Alzheimer's Disease

Alzheimer's disease (AD) is a devastating memory disorder affecting 32 million people worldwide (Drew et al., 2023). AD is characterized by aggregation of misfolded amyloid and tau proteins, disruption of neural circuits, and death of neural cells (Wang and Holtzman, 2020). Circuit dysfunction is a critical feature of disease progression in AD, and work in mouse AD models has demonstrated both hyperactivity (e.g., neocortex) and a reduction in the number of synaptic inputs (e.g., the hippocampus; Ye et al., 2022; Meftah and Gan, 2023).

Interestingly, the degree of neural circuitry impairment in AD may be sex-dependent. In humans, females are at a higher risk of developing AD compared with males (Nebel et al., 2018), and mouse studies have demonstrated sex-dependent changes to neural circuitry (e.g., in the hippocampus; Ye et al., 2022). However, few investigations have examined sex differences across brain regions in AD, leaving the extent of these variations largely unknown.

An area of keen interest is the subiculum, because this region is impaired early in AD pathogenesis (Kampmann, 2024) and is connected with many areas throughout the brain. Not only are neurons of the subiculum vulnerable to AD pathology, but AD-related changes in the interactions between this region and the rest of the brain vary by sex (Ye et al., 2022). Given this, a recent paper published in The Journal of Neuroscience aimed to document sex-dependent synaptic inputs to the subiculum in the most widely used mouse model of AD, the 5xFAD mouse line, that overexpress a form of the AD-linked amyloid protein harboring five mutations linked to familial AD.

Ye et al. (2024) compared AD …

Correspondence should be addressed to Brittany J. Dugan at brittany.dugan{at}mail.utoronto.ca.