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APOE genotype, sex, and ovariectomy influence anxiety‐like behaviors in an EFAD mouse model of Alzheimer’s disease
Author(s) -
Philippi Sarah M,
Taxier Lisa R,
York Jason,
LaDu Mary Jo,
Frick Karyn M
Publication year - 2020
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.047479
Subject(s) - apolipoprotein e , anxiety , genotype , estrogen , menopause , psychology , physiology , open field , medicine , elevated plus maze , habituation , disease , endocrinology , audiology , biology , psychiatry , genetics , gene
Background Behavioral changes accompanying the cognitive decline associated with Alzheimer’s disease (AD) are a growing concern. Symptoms of anxiety occur in 50‐75% of AD patients and increase throughout disease progression (Gustavson and Cummings, 2004; de Toledo et al., 2004). APOE4 genotype, the leading genetic risk factor for AD, may influence symptoms of anxiety in AD patients. Women APOE4 carriers are at greatest risk of developing AD, perhaps due in part to estrogen loss after menopause. However, contributions of APOE4 genotype, sex, and estrogen loss to anxiety in AD remain unclear. Method Effects of APOE status, sex, and ovariectomy (OVX) on anxiety‐like behaviors in an open field were measured. First, effects of sex and APOE genotype were examined in gonadally‐intact transgenic male and female mice expressing 5 familial AD mutations (5xFAD +/‐ ) and human APOE3 +/+ (E3FAD) or APOE4 +/+ (E4FAD). We next examined effects of APOE genotype and OVX in female EFADs. Mice were trained in object recognition (OR) and object placement (OP) tasks. Anxiety‐like behaviors were measured using open field (OF) data collected during the first habituation trial of OR or OP testing, during which mice had 5 minutes to explore an empty box (60 cm x 60 cm x 47 cm). Total distance traveled, average speed, and time spent in the center of the apparatus were measured. Result Sex influenced total distance and average speed, such that females traveled further at faster speeds than males. Only APOE genotype affected the time spent in the center of the OF apparatus, with E3FADs spending more time in the center than E4FADs, regardless of sex. OVXed E3FADs exhibited similar anxiety‐like behaviors as both intact and ovariectomized E4FADs. Conclusion E3FADs spent more time in the center of an OF than E4FADs of both sexes, suggesting an association between APOE4 and increased anxiety‐like behavior. OVX increased anxiety‐like behaviors in E3FADs to similar levels observed in intact and OVXed E4FADs, suggesting that the loss of estrogens in E3FAD females heightens anxiety‐like behaviors. These findings suggest significant interactions among APOE genotype, sex, and estrogens that may influence the incidence of anxiety in women with AD.