Roles of neuroestradiol in comorbid hyperexcitability and seizure susceptibility in Alzheimer Disease

项目总结

PROJECT SUMMARY Patients with Alzheimer Disease (AD) are at increased risk of seizures. Women show higher rates of AD than men, and loss of neuroprotective effects of ovarian hormones, such as estradiol, during and after menopause is considered to be a factor in cognitive and memory deficits of AD. However, estradiol is primarily linked to seizure- promoting effects in epilepsy. Estradiol thus may have both beneficial effects supporting cognitive function and detrimental (proconvulsant) effects in AD with comorbid seizures. Estradiol is synthesized from testosterone by the aromatase enzyme. Brain areas that are highly implicated in both AD and epilepsy, such as hippocampus and cortex, express high levels of aromatase in both males and females. Previous studies indicate that aromatase inhibition suppresses seizure susceptibility, but this effect has not been examined in the context of AD. Therefore, major gaps in knowledge remain regarding the role of brain-derived estradiol (neuroestradiol) in excitability, seizure susceptibility, and neuropathology in the comorbid relationship of seizures and AD. The overall objective of the proposed studies is to determine the role of neuroestradiol in modulating cellular excitability, synaptic transmission, and seizure susceptibility in a mouse model of AD that is prone to develop seizures. In Aim 1, we will use patch clamp electrophysiology, biochemistry, multilabel immunofluorescence microscopy, and a novel transgenic mouse model to determine the role of neuroestradiol in modulating cellular excitability and synaptic transmission in the hippocampus in AD and control mice. In Aim 2, we will use in vivo video-EEG and histological evaluation of neurodegeneration and gliosis to determine the role of neuroestradiol in modulating seizure susceptibility and seizure-induced neuropathology in the context of AD. These studies will have positive translational impact by providing new insights into the roles of neuroestradiol in hyperexcitability and seizures in AD in both males and females, enabling development of new therapeutic strategies to maximize seizure-suppressive effects while minimizing deleterious effects on cognition.