Impact of estrogen loss and replacement on GluN2B containing NMDARs, synaptic plasticity, and learning and memory in females using a novel transgenic rat model of Alzheimer’s Disease

 描述（由申请人提供）：阿尔茨海默病的目标是三分之二以上的女性比男性，可能是由于更年期激素丢失。临床和临床前数据支持17-雌二醇（E2）及其替代物在绝经后对神经元功能、淀粉样蛋白和tau病理学以及认知的有益作用。然而，目前尚不清楚E2如何在早期无症状和有症状的疾病进展中改善或维持认知功能的突触过程。突触外含GluN 2B的NMDAR的异常激活和突触内含GluN 2B的NMDAR的丢失是可溶性毒性A β受体增加和酪氨酸磷酸酶STEP活性增加的结果，被认为介导了症状前AD的突触缺陷。在转基因AD小鼠中，突触外含GluN 2B的NMDAR的激活增加似乎介导了海马中的脊丢失和LTP缺陷。因此，在疾病早期最小化异常突触外GluN 2B-NMDAR激活对于延迟其发作和减缓其进展至关重要。重要的是，雌激素样水平的血浆E2不仅增加棘密度和LTP，它选择性地增加突触电流介导的GluN 2B含有NMDAR是至关重要的E2增强的学习和记忆。E2的这些有益作用可以直接对抗增加的可溶性A β o的负面作用，但是E2是否可以在积累AD病理学的背景下刺激这些突触变化是一个悬而未决的问题。我们将使用一种新的AD转基因大鼠模型TgF 334-AD和脑切片电生理学结合学习和记忆行为来测试总体假设，即雌激素样E2替代可以通过增加突触和减少突触外含GluN 2B的NMDAR沿着其相关信号分子来增强OVX Tg雌性的突触功能，这将与增加突触可塑性以及学习和记忆有关。

 DESCRIPTION (provided by applicant): Alzheimer's disease targets two-thirds more women than men, likely a result of hormone loss during menopause. Clinical and preclinical data support beneficial roles of 17estradiol (E2) and its replacement post-menopause on neuronal function, amyloid and tau pathology, and cognition. However, it is unknown how E2 improves or maintains synaptic processes underlying cognitive function throughout early asymptomatic and symptomatic disease progression. Abnormal activation of extrasynaptic GluN2B-containing NMDARs and loss of synaptic GluN2Bcontaining NMDAR as a consequence of increased soluble toxic Aand increased activity of the tyrosine phosphatase STEP are believed to mediate synaptic deficits in presymptomatic AD. The increased activation of extrasynaptic GluN2B-containing NMDARs appears to mediate spine loss and LTP deficits in hippocampus in transgenic AD mice. Therefore, minimizing aberrant extrasynaptic GluN2B-NMDAR activation early in the disease is critical to delaying its onset and slowing its progression. Importantly, proestrous-like levels of plasma E2 not only increases spine density and LTP, it selectively increases synaptic current mediated by GluN2Bcontaining NMDARs that are critical for the E2-enhanced learning and memory. These beneficial effects of E2 could directly oppose the negative effects of increased soluble Ao, but whether E2 can stimulate these synaptic changes in the context of accumulating AD pathology is an open question. We will use a novel transgenic rat model of AD, TgF334-AD, and brain slice electrophysiology combined with learning and memory behavior to test the overarching hypothesis that that proestrous-like E2 replacement can heighten synaptic function in OVX Tg females by increasing synaptic and decreasing extrasynaptic GluN2B-containing NMDARs along with their associated signaling molecules, which will be linked to increased synaptic plasticity and learning and memory.