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

项目总结 阿尔茨海默病(AD)患者癫痫发作的风险增加。女性患AD的比例高于女性 绝经期间和绝经后卵巢激素(如雌二醇)的神经保护作用的丧失 被认为是阿尔茨海默病认知和记忆障碍的一个因素。然而，雌二醇主要与癫痫有关- 对癫痫有促进作用。因此，雌二醇可能既有支持认知功能的有益效果，也有 阿尔茨海默病合并癫痫发作的有害(促惊厥)作用。雌二醇是由睾酮合成的。 芳香酶。与阿尔茨海默病和癫痫高度相关的大脑区域，如海马体 和皮层，在雄性和雌性中都表达高水平的芳香酶。此前的研究表明， 芳香酶抑制抑制癫痫敏感性，但这种影响尚未在 广告。因此，关于脑源性雌二醇(神经雌二醇)在脑血管疾病中的作用仍然存在主要的认识空白。 癫痫与阿尔茨海默病共病关系中的兴奋性、癫痫敏感性和神经病理学。这个 拟议研究的总体目标是确定神经雌激素在调节细胞内的作用。 易发生阿尔茨海默病小鼠模型的兴奋性、突触传递和癫痫敏感性 癫痫发作。在目标1中，我们将使用膜片钳电生理学、生物化学、多标记免疫荧光 显微镜和一种新的转基因小鼠模型来确定神经雌二醇在调节细胞中的作用 阿尔茨海默病小鼠和对照组小鼠海马区兴奋性和突触传递。在目标2中，我们将在体内使用 视频脑电和组织学评估神经退行性变和胶质细胞增生症以确定神经雌激素的作用 在阿尔茨海默病背景下调节癫痫敏感性和癫痫诱发的神经病理学。这些研究将 通过对神经雌二醇在过度兴奋中的作用提供新的见解，产生积极的翻译影响 以及男性和女性AD的癫痫发作，使新的治疗策略得以开发，以最大限度地 抑制癫痫发作的效果，同时将对认知的有害影响降至最低。

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.