Effects of long‐term oral treatment with a novel estrogen receptor beta agonist on memory, vasomotor, and anxiety outcomes in an EFAD mouse model of Alzheimer’s disease

Abstract Background The prevalence and severity of Alzheimer’s disease (AD) are increased by female sex, apolipoprotein E (APOE) genotype, and age, such that postmenopausal female carriers of the Apoe4 allele are at greater risk of developing AD than age‐matched males. Although estrogen therapy shows promise in preventing and reducing menopause‐ and AD‐related symptoms, activation of estrogen receptor alpha (ERa) is associated with increased risk for health concerns, such as breast cancer. Therefore, treatments more selective for estrogen receptor beta (ERb) may provide estrogen‐related health benefits without the risks of activating ERa. Long‐term or acute treatment of wild‐type mice with the novel ERb agonist, EGX358, improves memory and reduces drug‐induced vasomotor alterations. However, efficacy of this compound in an AD model is unknown. Method Female APOE‐TR +/+ /5xFAD +/− (EFAD) mice expressed five familial AD and were homozygous for human APOE3 (E3FAD) or heterozygous for APOE3 and APOE4 (E3/4FAD). Mice were ovariectomized at 5 months of age and then treated orally with vehicle (1% DMSO) or EGX358 (10 mg/kg/day) via hydrogel for 8 weeks. Mice were weighed weekly and tested for spatial and object memory in the object placement (OP) and object recognition (OR) tasks, respectively. Anxiety‐like behaviors were also tested in the open field and elevated plus maze, and vasomotor symptoms were assessed via tail temperature following injection of the tachykinin receptor 3 agonist, senktide. Result EGX358 significantly enhanced OR memory in both E3FAD and E3/4FAD mice. However, treatment did not affect OP memory or anxiety in the open field or elevated plus maze. Interestingly, there were significant genotype differences in open field, vasomotor response, and body weight such that E3/4FADs spent more time in the center of open field, had a greater increase in tail temperature following senktide injection, and gained more weight compared to E3FADs. Conclusion Our findings indicate a potential for ERβ‐specific estrogen treatment to improve memory for the identity of objects. Unexpected genotype differences indicate the need to further study how APOE genotype affects anxiety and metabolic outcomes in AD.