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

神经雌二醇在阿尔茨海默病共病过度兴奋和癫痫易感性中的作用

基本信息

批准号：
10453981
负责人：
Catherine A Christian-Hinman
金额：
$ 41.79万
依托单位：
UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-15 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10453981
关键词：
APP-PS1 Acute Address Adult Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease patient Animal Model Area Aromatase Aromatase Inhibition Aromatase Inhibitors Biochemistry Brain Cells Cognition Cognitive deficits Conflict (Psychology)Cre lox recombination system Data Development Dose Early Onset Alzheimer Disease Electroencephalography Electrophysiology (science)Enzymes Epilepsy Estradiol Estrogen Receptors Estrogens Etiology Evaluation Female Functional disorder Genetic Gliosis Hippocampus (Brain)Histologic Histopathology Immunofluorescence Microscopy Injections Kainic Acid Knowledge Letrozole Link Long-Term Effects LoxP-flanked allele Measurement Mediating Memory Memory impairment Menopause Modeling Molecular Monitor Mus Nerve Degeneration Neurons Ovarian Ovarian hormone Patients Pharmacology Play Predisposition Production Prosencephalon Rattus Regimen Reporting Research Risk Role Seizures Slice Source Symptoms Synapses Synaptic Transmission Tamoxifen Testing Testosterone Transgenic Mice Wild Type Mouse Woman Work cell type cognitive benefits cognitive function comorbidity disorder control excitatory neuron in vivo insight interest knock-down male men mouse model neuropathology novel novel therapeutic intervention novel therapeutics patch clamp preservation relating to nervous system selective expression sex synaptic function translational impact

项目摘要

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.

项目摘要阿尔茨海默病（AD）患者癫痫发作的风险增加。女性的AD发病率高于在绝经期和绝经后，被认为是AD认知和记忆缺陷的一个因素。然而，雌二醇主要与癫痫发作有关对癫痫有促进作用。因此，雌二醇可能具有支持认知功能的有益效果，在AD与共病癫痫发作中的有害（促惊厥）作用。雌二醇是由睾酮合成的，芳香酶与AD和癫痫高度相关的大脑区域，如海马和皮质，在雄性和雌性中表达高水平的芳香化酶。先前的研究表明，芳香化酶抑制剂抑制癫痫发作的易感性，但这种作用尚未在 AD.因此，关于脑源性雌二醇（神经雌二醇）的作用，兴奋性、癫痫易感性和癫痫与AD共病关系中的神经病理学。的本研究的总体目标是确定神经雌二醇在调节细胞凋亡中的作用。兴奋性、突触传递和癫痫发作易感性在AD小鼠模型中，癫痫发作。目的一：应用膜片钳电生理、生物化学、多标记免疫荧光技术，显微镜下，和一种新的转基因小鼠模型，以确定神经雌二醇在调节细胞的作用，兴奋性和突触传递在AD和对照小鼠的海马。在目标2中，我们将使用体内视频脑电图和神经变性和神经胶质增生的组织学评估，以确定神经雌二醇的作用在AD背景下调节癫痫发作易感性和癫痫诱导的神经病理学。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，在男性和女性中，AD的癫痫发作，使开发新的治疗策略，在最小化对认知的有害影响的同时，抑制神经功能的作用。