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GONADAL HORMONES MODULATE HIPPOCAMPAL NUCLEAR DEK EXPRESSION IN ADULT MICE AND RATS

Alzheimer’s Disease (AD) is currently the 6th leading cause of death in the United States, and is the most common cause of dementia. Women are more likely than men to be diagnosed with AD. The cause of this discrepancy is not known; however, the loss of circulating estrogen after menopause is hypothesized to be a leading factor for women’s increased risk of AD. Estrogen is considered neuroprotective; it can ameliorate the effects of brain injury, contribute to DNA repair in mitochondria, and maintain synapse number and spine density in the hippocampus. Our laboratory is investigating the role of an estrogen receptor alpha (ERα) target gene, DEK, as a novel player in Alzheimer’s disease and age‐related dementias. DEK is a nuclear chromatin phosphoprotein that is expressed throughout the brain, and is prominently expressed in the hippocampus, a brain region important for learning and memory. Preliminary data indicate that DEK loss in vitro and in vivo results in AD and dementia‐like phenotypes, such as cell death, increased total tau and phosphorylated tau expression, DNA damage, and decreased hippocampal microtubule associated protein (MAP2) expression. These findings suggest a neuroprotective role of DEK. Given that DEK is an ERα target gene, we postulated that DEK expression in the brain would be modulated by circulating levels of estrogen. We specifically hypothesized that loss of estrogens would decrease DEK expression in the hippocampus. To study this, we used a surgical rodent model of menopause, ovariectomy (OVX), to remove the main source of circulating estrogen in female rats. OVX was performed in 3‐month‐old Sprague Dawley rats. Cell counts and optical density analysis were done using NIH Image J. We found that following two months ovariectomy, DEK expression was decreased in the hippocampus of adult female rats. Besides estrogen, the gonadal hormones testosterone and progesterone can exhibit neuroprotective effects as well. Therefore, we included males in our next experiment in order to determine if gonadal hormone depletion in males would also affect DEK expression. Similar to rats, gonadectomy decreased hippocampal DEK expression in adult male and female mice. Interestingly, OVX significantly decreased DEK expression relative to castration in the CA1 and CA3 regions of the hippocampus. These findings suggest that the impact of gonadal hormone loss on DEK expression is evident across species. We do not yet know the effect of specific gonadal hormonal administration (e.g., E2 or testosterone) on central DEK expression in castrated males and OVX females; therefore, future studies will explore this. Our results suggest that biological factors such as circulating hormones can affect the expression of DEK, whose deficiency may be linked with neurodegeneration and brain aging in dementia and AD.