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（由适用提供）：阿尔茨海默氏病的目标是男性的三分之二，这可能是由于绝经期间的马内损失的结果。临床和临床前数据支持17Eradiol（E2）的有益作用及其在神经元功能，淀粉样蛋白和TAU病理学以及认知的培训后替代。但是，尚不清楚E2如何改善或维持在早期不对称和有症状性疾病进展的认知功能的基础突触过程。由于可溶性毒性A的增加，含有突触外glun2b的NMDAR的异常激活以及含酪氨酸磷酸酶步骤的活性增加，含有突触的NMDAR的含有突触的NMDAR和突触的增加，因此可以增加蛋白酶磷酸酶的活性。在转基因AD小鼠的海马中，含有性lun2b的NMDAR的激活增加似乎增加了脊柱损失。因此，在疾病早期，最大程度地减少了异常的环外glun2b-nMDAR激活对于延迟其发作和减缓其进展至关重要。重要的是，类似阳离子的等离子E2水平不仅增加了脊柱密度和LTP，还可以选择地增加了由Glun2B的NMDAR介导的突触电流，这对于E2增强学习和记忆至关重要。 E2的这些有益作用可以直接反对增加固体AO的负面影响，但是在积累AD病理学的背景下，E2是否可以刺激这些综合变化是一个悬而未决的问题。我们将使用一种新型的AD，TGF334-AD和脑切片电生理学的转基因大鼠模型与学习和记忆行为相结合，以测试总体上的假设，即主动的E2替换可以通过增加突触的ovx TG中的突触功能来增强突触和降低的突触，并降低脑外的粘液型NM，并与他们的脑外孔相关的nm nm nm nms nm nms nms nms nm nm nms nm nms nm nm nms nms nm nm nm nm nms nm nm nms nm nm nms nm nm nms nm nm nm nm nm nms。增加突触可塑性，学习和记忆。