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

使用新型阿尔茨海默病转基因大鼠模型，研究雌激素损失和替代对含有 NMDAR 的 GluN2B、突触可塑性以及女性学习和记忆的影响

• 批准号: 9128361
• 负责人: LORI Lynn MCMAHON
• 金额: $ 22.05万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9128361
• 关键词: Age; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease risk; Amyloid; Award; Behavior; Brain; Clinical; Clinical Research; Cognition; Cognitive; Corpus striatum structure; Data; Development; Diagnosis; Disease; Disease Progression; Electrophysiology (science); Estradiol; Estrogens; Female; Functional disorder; Future; Genetic; Health; Hippocampus (Brain); Hormones; Human; Impaired cognition; Incidence; Investigation; Knowledge; Lead; Learning; Life Expectancy; Link; Longevity; Mediating; Memory; Memory impairment; Menopause; Modeling; Mus; Neurons; Onset of illness; Ovarian; Ovarian hormone; Ovariectomy; Pathology; Performance; Phosphorylation; Physiology; Plasma; Postmenopause; Process; Protein Dephosphorylation; Protein Tyrosine Phosphatase; Pyramidal Cells; Rattus; Risk Factors; Role; Sex Bias; Signal Pathway; Signaling Molecule; Slice; Staging; Synapses; Synaptic plasticity; Testing; Therapeutic; Time; Transgenic Organisms; Tyrosine; Vertebral column; Woman; Women' s Health; aged; amyloid pathology; cognitive function; cognitive performance; density; deprivation; gender disparity; improved; inorganic phosphate; men; mouse model; novel; object recognition; pre-clinical; preclinical study; protective effect; public health relevance; synaptic function; tau Proteins; tau aggregation; young adult

 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.

 描述(申请人提供)：阿尔茨海默病患者中女性比男性多三分之二，很可能是由于更年期荷尔蒙丢失所致。临床和临床前数据支持17雌二醇(E2)及其绝经后替代品在神经元功能、淀粉样蛋白和tau病理以及认知方面的有益作用。然而，在早期无症状和有症状的疾病进展过程中，E2如何改善或维持潜在的认知功能的突触过程尚不清楚。突触外含有GluN2B的NMDAR的异常激活和含有NMDAR的突触GluN2B的丢失是症状前AD的突触缺陷的原因之一，这是由于可溶性毒性A增加和酪氨酸磷酸酶步骤的活性增加所致。突触外含GluN2B的NMDARs的激活增加似乎介导了转基因AD小鼠的脊椎丢失和海马LTP缺陷。因此，在疾病的早期尽量减少异常的突触外GluN2B-NMDAR的激活对于延缓其发病和减缓其进展至关重要。重要的是，发情样水平的血浆E2不仅增加了脊椎密度和LTP，而且选择性地增加了含有GluN2B的NMDAR介导的突触电流，这对E2增强的学习和记忆至关重要。E2的这些有益作用可以直接对抗可溶性Ao增加的负面影响，但在AD病理积累的背景下，E2是否能刺激这些突触变化还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TgF334-AD，并结合学习和记忆行为的脑片电生理学来测试主要假设，即发情样E2替换可以通过增加突触和减少突触外含有GluN2B的NMDAR及其相关信号分子来增强OVX TG女性的突触功能，这将与突触可塑性和学习记忆的增加有关。