Effects of a Novel Estrogen Receptor Beta Agonist on Proteins Associated with Memory in an Alzheimer’s Mouse Model

Beaty, Hailey, College of Letters & Science, Frick, Karyn, Mentor, Poster Presentation, Projects, Psychology, School and College, Schwabe, Miranda, Student

Hailey Beaty, “Effects of a Novel Estrogen Receptor Beta Agonist on Proteins Associated with Memory in an Alzheimer’s Mouse Model”
Mentors: Karyn Frick and Miranda Schwabe, Psychology
Poster #21

Alzheimer’s disease (AD) causes severe memory loss and other cognitive difficulties. Relative to men, women are at significantly greater risk of developing AD, particularly those who carry two copies of the E4 allele of the lipid-carrying protein apolipoprotein E (APOE). Estrogen loss at menopause may contribute to this increased risk in women, but estrogen therapy is not recommended to reduce memory loss due to side effects caused by estrogen binding to the alpha subtype of the estrogen receptor. Activation of the beta subtype of estrogen receptor (ERb) facilitates memory without causing harmful side effects, so could be a novel treatment strategy for women with AD. This study was designed to determine the extent to which a novel ERb agonist, EGX358, could improve memory (data not shown) and affect proteins associated with memory in a transgenic mouse model of AD. Subjects were female mice engineered to express 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). The Frick lab previously demonstrated that estrogen alleviates memory deficits in female E3FAD and E3/4FAD mice and that EGX358 facilitates memory formation in wild-type female mice. Here, mice received oral administration of vehicle or EGX358 for 8 weeks, during which time memory and other behaviors were tested. At the conclusion of testing, tissue was collected from the dorsal hippocampus, a brain region necessary for memory consolidation. We used western blots to examine levels of phosphorylated CREB (a transcription factor that assists in long-term memories), as well as synaptophysin and PSD95, proteins associated with increased synaptic plasticity and synaptic connections. We expect that mice of both APOE genotypes treated with EGX358 will have increased levels of p CREB, synaptophysin, and PSD95 compared to vehicle-treated mice. This research will provide new insights into the potential for selective estrogen receptor modulators to influence the molecular mechanisms associated with memory in a mouse model of Alzheimer’s disease, which could assist in the development of next-generation estrogen treatments that reduce the risk of dementia.