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: 7495623
• 负责人: KEBRETEN F MANAYE
• 金额: $ 29.43万
• 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/7495623
• 关键词: Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Amygdaloid structure; Amyloid; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Amyloid deposition; Arts; Astrocytes; Astrocytosis; Brain; Brain Stem; Brain region; Cessation of life; Characteristics; Chromosome Pairing; Chronic; Collaborations; Complex; Dementia; Deposition; Development; Dose; Estradiol; Exhibits; Female; Fiber; Functional disorder; Gender; Gerontology; Gliosis; Goals; Gonadal Hormones; Hippocampal Formation; Hippocampus (Brain); Histologic; Human; Inherited; Institutes; Laboratories; Lead; Longevity; Microglia; Modeling; Mus; Mutate; Mutation; Nerve Degeneration; Neurofibrillary Tangles; Neuroglia; Neurons; Numbers; Outcome Study; Oxidative Stress; Pathogenesis; Pathology; Pathway interactions; Peptides; Persons; Play; Pontine structure; Population; Proteins; Role; Senile Plaques; Sex Characteristics; Structure; Structure of molecular layer of cerebellar cortex; Synapses; System; Techniques; Testing; Therapeutic; Thinking; Transgenic Model; Transgenic Organisms; Variant; Weaning; Wild Type Mouse; age effect; aged; base; cerebral atrophy; familial Alzheimer disease; gene cloning; indexing; locus ceruleus structure; male; medical schools; middle age; mutant; neocortical; neuropathology; neuroprotection; noradrenergic; presenilin; presenilin-1; research study; response

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）已被认为是导致老年痴呆症的主要原因。 老年痴呆症和死亡。最有特征的发现包括新皮质和 海马神经病理学，包括含有 β-淀粉样蛋白的神经炎斑块、神经原纤维缠结、突触丧失、神经胶质增生以及严重的大脑和皮质萎缩，所有这些都可能因氧化应激而加剧。此后，转基因小鼠模型被开发出来，模拟 AD 中的一些神经病理学发现。该项目具体目标1的主要目标是使用共表达突变淀粉样前体蛋白（APP）和突变早老素1（PS1）的双转基因小鼠模型来表征神经元通路中与年龄和性别相关的改变，特别是来自桥脑脑干的去甲肾上腺素能投射。具体来说，我们将量化 β-淀粉样蛋白（淀粉样蛋白负载）的水平以及 dtg APP/PS1 小鼠表现出的程度：蓝斑 (LC) 以及杏仁核和海马中去甲肾上腺素能末端的神经元变性； LC 和投影视野中的小胶质细胞增多症和星形细胞增多症。具体目标 2 将评估 17-β 雌二醇 (E2) 针对这种 AD 型神经病理学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。 我们假设长期 E2 治疗将减少淀粉负荷和其他神经退行性指标。我们将使用最先进的神经立体学技术来评估衰老、性别和 E2 对 dtg APP/PS1 小鼠离散大脑区域的 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治疗管理新策略奠定基础。