APOE genotype and sex influence memory and dendritic spine density in an EFAD mouse model of Alzheimer’s disease

Abstract

AbstractBackgroundWomen carriers of the APOE4 genotype, which is the leading genetic risk factor for late‐onset Alzheimer’s disease (AD), are more likely than women carriers of other APOE genotypes and men of any APOE genotype to develop AD. However, factors underlying the interaction between APOE genotype and sex are not well characterized. The goal of this study was to examine the effects of sex and APOE genotype on memory function and dendritic spine density in a mouse model of AD.MethodsSix month‐old gonadally‐intact male and female transgenic (Tg) mice expressing 5 familial AD mutations (5xFAD+/‐) and human APOE3 +/+ (E3FAD) or APOE4 +/+ (E4FAD) were trained on object recognition (OR) and object placement (OP) tasks designed to test object recognition and spatial memory formation. Memory for previously seen objects or locations was tested 24 or 4 hours later, respectively. Two weeks after the conclusion of behavioral testing, mice were retrained with novel objects, and brains were collected for Golgi staining. Following staining, apical and basal dendritic spines in the dorsal hippocampus (DH) and medial prefrontal cortex (mPFC) were counted and classified by morphological type.ResultsMale E3FAD mice exhibited intact memory for previously seen objects or locations, whereas male E4FADs and female E3FAD or E4FAD mice did not. The density of total, mushroom, and stubby spines on basal CA1 and mPFC dendrites was lower for E4FAD mice of both sexes compared to E3FAD mice. Preliminary data suggest a similar pattern for mPFC apical spine density.ConclusionsThese data suggest that APOE genotype and sex influence object recognition and spatial memory formation, and that APOE4 genotype is associated with reduced density of mature and immature spines in CA1 and the mPFC.