Effects of a Novel Estrogen Receptor Beta Agonist and APOE Genotype on Dendritic Spine Density in a Mouse Model of Alzheimer’s Disease
Mentor 1
Karyn Frick
Start Date
28-4-2023 12:00 AM
Description
Women are at greater risk of developing AD than men, particularly those that express the gene apolipoprotein 4 (APOE4). Female APOE4 carriers have the highest AD risk. One way to assess effects of APOE4 expression on AD-related neuropathology is to measure dendritic spine density as an index of synapse integrity. Synapse loss is directly implicated in Alzheimer’s Disease (AD). In a transgenic model of AD, mice with one or two copies of APOE4 have decreased dendritic spine density in the dorsal hippocampus (DH) and medial prefrontal cortex (mPFC), regions crucial for memory. In mice carrying one or two copies of the human APOE allele APOE3, treatment with estrogen reverses spine density loss (Taxier et al., 2022), but in humans estrogen therapies are associated with increased cancer risk via activation of estrogen receptor alpha (ERα). Estrogen receptor beta (ER) promotes memory yet does not cause cancer. Here, we investigated a novel ER agonist, EGX358, as a safer alternative to traditional estrogen therapy. Five-month-old female mice that were homozygous for APOE3 or carried one copy of APOE4 were ovariectomized and treated orally with vehicle (1% DMSO) or EGX358 (10 mg/kg/day) for 9 weeks. EGX358 improved object recognition memory in both genotypes. After a final EGX358 treatment, brains were collected 1-3 hours later, with half Golgi stained for spine density counting in the DH. Dendritic reconstructions were made using Neurolucida software, apical and basal dendritic segments were imaged at 100x, and total spines as well as subgroups (thin, stubby, mushroom) were counted and averaged relative to segment length. Preliminary results suggest no significant effect of treatment or genotype on total spines or subgroups in DH, however, data collection is ongoing. This work is important to establishing potential utility of EGX358 as an AD therapeutic and to better understand the neuropathology of AD.
Effects of a Novel Estrogen Receptor Beta Agonist and APOE Genotype on Dendritic Spine Density in a Mouse Model of Alzheimer’s Disease
Women are at greater risk of developing AD than men, particularly those that express the gene apolipoprotein 4 (APOE4). Female APOE4 carriers have the highest AD risk. One way to assess effects of APOE4 expression on AD-related neuropathology is to measure dendritic spine density as an index of synapse integrity. Synapse loss is directly implicated in Alzheimer’s Disease (AD). In a transgenic model of AD, mice with one or two copies of APOE4 have decreased dendritic spine density in the dorsal hippocampus (DH) and medial prefrontal cortex (mPFC), regions crucial for memory. In mice carrying one or two copies of the human APOE allele APOE3, treatment with estrogen reverses spine density loss (Taxier et al., 2022), but in humans estrogen therapies are associated with increased cancer risk via activation of estrogen receptor alpha (ERα). Estrogen receptor beta (ER) promotes memory yet does not cause cancer. Here, we investigated a novel ER agonist, EGX358, as a safer alternative to traditional estrogen therapy. Five-month-old female mice that were homozygous for APOE3 or carried one copy of APOE4 were ovariectomized and treated orally with vehicle (1% DMSO) or EGX358 (10 mg/kg/day) for 9 weeks. EGX358 improved object recognition memory in both genotypes. After a final EGX358 treatment, brains were collected 1-3 hours later, with half Golgi stained for spine density counting in the DH. Dendritic reconstructions were made using Neurolucida software, apical and basal dendritic segments were imaged at 100x, and total spines as well as subgroups (thin, stubby, mushroom) were counted and averaged relative to segment length. Preliminary results suggest no significant effect of treatment or genotype on total spines or subgroups in DH, however, data collection is ongoing. This work is important to establishing potential utility of EGX358 as an AD therapeutic and to better understand the neuropathology of AD.
