Impact of Aging and Gender on the Noradrenergic System in a Transgenic Model

转基因模型中衰老和性别对去甲肾上腺素能系统的影响

• 批准号: 7312782
• 负责人: KEBRETEN F MANAYE
• 金额: $ 22.17万
• 依托单位: HOWARD UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7312782
• 关键词: Alzheimer' s disease; age difference; amygdala; amyloid proteins; brain mapping; brain morphology; cooperative study; disease /disorder model; estradiol; gender difference; genetically modified animals; hippocampus; histopathology; laboratory mouse; locus coeruleus; neural degeneration; neuropathology; neuroprotectants; norepinephrine; pons; presenilin

In the past two decades Alzheimer's disease (AD) has been recognized as a dominant cause of dementia and death in aged populations. The most characteristic findings include neocortical and hippocampal neuropathology, with beta-amyloid-containing neuritic plaques, neurofibrillary tangles, synapse loss, gliosis, and severe brain and cortical atrophy, all of which may be exacerbated by oxidative stress. Transgenic murine models have since been developed which mimic some of the neuropathological findings in AD. The major goals of Specific Aim 1 in this project are to use the double transgenic murine model co-expressing mutant amyloid precursor protein (APP) and mutant presenilin 1 (PS1) to characterize age- and gender-related alterations in neuronal pathways, particularly the noradrenergic projections from the pontine brainstem. Specifically, we will quantify the level of beta-amyloid (amyload) and the extent to which dtg APP/PS1 mice exhibit: neuronal degeneration in the locus coeruleus (LC) and noradrenergic terminals in the amygdala and hippocampus; microgliosis and astrocytosis in LC and projection fields. Specific Aim 2 will assess the ability of 17-beta estradiol (E2) to provide neuroprotection against this AD-type neuropathology. These studies will be performed in middle-aged ovariectomized mice. We hypothesize that chronic E2 treatment will reduce the amyload and other neurodegenerative indices. We will use state-of-the-art neurostereological techniques to assess the effects of aging, gender, and E2 on AD-type neuropathology in discrete brain regions of dtg APP/PS1 mice. The results will confirm the noradrenergic pathophysiology in the model of AD-like amyloid deposition, and establish a basis for the development of new strategies for the therapeutic management of AD.

在过去的二十年中，阿尔茨海默病（AD）已被认为是阿尔茨海默病的主要原因。 老年痴呆症和死亡。最典型的发现包括新皮质和 海马神经病理学，具有含β-淀粉样蛋白的神经炎斑、神经纤维缠结、突触丧失、神经胶质增生和严重的脑和皮质萎缩，所有这些都可能因氧化应激而加重。转基因鼠模型已经被开发，其模拟AD中的一些神经病理学发现。在这个项目中，具体目标1的主要目标是使用双转基因小鼠模型共表达突变淀粉样前体蛋白（APP）和突变早老素1（PS1），以表征年龄和性别相关的神经元通路的变化，特别是从脑桥脑干的去甲肾上腺素能投射。具体而言，我们将量化β-淀粉样蛋白（amylload）的水平和dtg APP/PS1小鼠表现出的程度：蓝斑（LC）和杏仁核和海马中的去甲肾上腺素能末梢的神经元变性; LC和投射野中的小胶质细胞增生和星形胶质细胞增生。具体目标2将评估17-β雌二醇（E2）对AD型神经病理提供神经保护的能力。这些研究将在中年卵巢切除小鼠中进行。 我们推测，长期E2治疗将减少amyload和其他神经退行性指标。我们将使用最先进的神经体视学技术来评估年龄、性别和E2对dtg APP/PS1小鼠离散脑区AD型神经病理学的影响。该结果将证实AD样淀粉样蛋白沉积模型中的去甲肾上腺素能病理生理学，并为开发AD治疗管理的新策略奠定基础。