Investigating the Impact of NMDA Receptor Organization and Biological Sex in the APPswe/PS1dE9 Mouse Model of Alzheimer’s Disease

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by memory loss and cognitive decline, with women being disproportionately affected in both prevalence and severity. A key feature of AD is synaptic loss, particularly around amyloid-β (Aβ) aggregates, which correlates strongly with the severity of dementia. Oligomeric Aβ is believed to be the primary driver of synaptic dysfunction by impairing excitatory neurotransmission through interactions with synaptic receptors, including N-methyl-D-aspartate (NMDA) receptors. However, the influence of sex on these synaptic changes and NMDA receptor mislocalization in AD is not well understood. This study examined potential sex-specific differences in synaptotoxicity and the role of extrasynaptic GluN2B-containing NMDA receptors in AD pathogenesis using the APP/PS1 double transgenic mouse model. Although both male and female mice showed a similar amyloid burden and cognitive impairments, synaptic alterations were slightly less severe in females, suggesting subtle sex differences in synaptic pathology. Both sexes exhibited the mislocalization of GluN2B subunits to extrasynaptic areas, which was linked to reduced PSD-95 levels and the synaptic accumulation of Aβ_1-42. Intrahippocampal injections of DL-TBOA confirmed the role of extrasynaptic GluN2B-containing NMDA receptors in memory dysfunction. These findings emphasize the importance of targeting synaptic receptor trafficking to address AD-related memory deficits, potentially offering a therapeutic approach for both sexes.