Effects of a Novel Estrogen Receptor β Agonist on Memory, Anxiety, and Vasomotor Symptoms in an Alzheimer’s Mouse Model

Age, biological sex, and apolipoprotein E (APOE) genotype are associated with Alzheimer’s disease (AD) risk. Although the APOE3 allele confers neutral risk, APOE4 is strongly linked to increased AD risk and severity, especially in post-menopausal women. Estrogen loss at menopause may contribute to women’s elevated AD risk, and is further associated with symptoms such as anxiety and hot flashes. Although effective against these symptoms and risks, estrogen therapies also promote risk of health concerns such as breast cancer by activating estrogen receptor ⍺. However, estrogen receptor β (ERβ) activation enhances memory and reduces hot flashes preclinically without harmful side effects. Therefore, ERβ agonists might be useful therapeutics for reducing menopausal symptoms and AD risk in women. Here, we tested our novel ERβ agonist, EGX358, in ovariectomized female mice carrying five familial Alzheimer’s disease gene mutations as well as two copies of human APOE3 or one copy of APOE3 and APOE4 (E3FAD, E3/4FAD). Vehicle (1% DMSO) or EGX358 (10 mg/kg/day) were delivered orally via hydrogels for 8 weeks before mice were tested for memory, anxiety-like behaviors, and hot flashes. Memory was tested in object placement (OP) and object recognition (OR) tests, wherein the ability to identify a moved or novel object was measured, respectively. Time spent in the open areas of the elevated plus maze and open field (OF) tests were measured for anxiety-like behavior. Tails were thermally imaged for vasomotor symptoms following subcutaneous administration of senktide, a tachykinin receptor agonist which induces hot flash-like responses in rodents. EGX358 improved OR, but not OP, memory in both genotypes but had little effect on anxiety-like behaviors or tail temperature, although E3/4FADs spent more time in the center of the OF but were more sensitive to drug-induced vasomotor symptoms than E3FADs. Overall, EGX358 effectively enhances object recognition memory, even in an AD model