Sexual Dimorphism, Altered Hippocampal Glutamatergic Neurotransmission and Cognitive Impairment in APP Knock-In Mice

Background It is well established that glutamatergic neurotransmission plays an essential role in learning and memory. Previous studies indicate that glutamate dynamics shift with Alzheimer’s disease (AD) progression, contributing to negative cognitive outcomes. Objective In this study, we characterized hippocampal glutamatergic signaling with age and disease progression in a knock-in mouse model of AD (APP NL-F/NL-F ). Methods At 2-4 and 18+ months old, male and female APP NL/NL , APP NL-F/NL-F , and C57BL/6 mice underwent cognitive assessment using Morris water maze (MWM) and Novel Object Recognition (NOR). Then, basal and 70 mM KCl stimulus-evoked glutamate release was measured in the dentate gyrus (DG), CA3, and CA1 regions of the hippocampus using a glutamate-selective microelectrode in anesthetized mice. Results Glutamate recordings support elevated stimulus-evoked glutamate release in the DG and CA3 of young APP NL-F/NL-F male mice that declined with age compared to age-matched control mice. Young female APP NL-F/NL-F mice exhibited increased glutamate clearance in the CA1 that slowed with age compared to age-matched control mice. Male and female APP NL-F/NL-F mice exhibited decreased CA1 basal glutamate levels, while males also showed depletion in the CA3. Cognitive assessment demonstrated impaired spatial cognition in aged male and female APP NL-F/NL-F mice, but only aged females displayed recognition memory deficits compared to age-matched control mice. Conclusions These findings confirm a sex-dependent hyper-to-hypoactivation glutamatergic paradigm in APP NL-F/NL-F mice. Further, data illustrate a sexually dimorphic biological aging process resulting in a more severe cognitive phenotype for female APP NL-F/NL-F mice than their male counterparts. Research outcomes mirror that of human AD pathology and provide further evidence of divergent AD pathogenesis between sexes.