Event Title

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

Location

Karyn Frick

Start Date

10-5-2022 10:00 AM

Description

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 the E4 allele of 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 harmful side effects, so could be a treatment strategy for women with AD. This study investigated 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). 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, 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.

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May 10th, 10:00 AM

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

Karyn Frick

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 the E4 allele of 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 harmful side effects, so could be a treatment strategy for women with AD. This study investigated 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). 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, 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.