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，阿尔茨海默氏病（AD）被认为是 老年人群的痴呆和死亡。最具特征性的发现包括新皮质和 海马神经病理学，具有含有β淀粉样蛋白的神经斑块，神经原纤维缠结，突触丧失，神经胶质病以及严重的脑和皮质萎缩，所有这些都可能因氧化应激加剧。此后，已经开发了转基因鼠模型，这些模型模仿了AD中的一些神经病理学发现。该项目中特定目标1的主要目标是使用双转基因鼠模型共表达突变体淀粉样蛋白前体蛋白（APP）和突变体presenilin 1（PS1）来表征神经元途径的年龄和性别相关的变化，尤其是来自pontine brainstem的甲肾上腺素能投射。具体而言，我们将量化β-淀粉样蛋白（AMYLOAD）的水平以及DTG APP/PS1小鼠展示的程度：层层院（LC）中的神经元变性和杏仁核和海马的甲肾上腺素能末端； LC和投影场中的小胶质细胞增多和星形细胞增多症。具体目标2将评估17β雌二醇（E2）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。 我们假设慢性E2治疗将减少Amyload和其他神经退行性指数。我们将使用最先进的神经学技术来评估DTG APP/PS1小鼠离散大脑区域中衰老，性别和E2对AD型神经病理学的影响。结果将在AD样淀粉样蛋白沉积模型中证实去甲肾上腺素能的病理生理学，并为开发AD治疗管理的新策略建立基础。