The effect of life span modifying interventions on Alzheimer's Disease in Drosophila and Mice.

项目摘要/摘要：(最多30行) 这项提案的总体目标是开发基因和药物干预措施，以延迟 阿尔茨海默病(AD)的发生和发展。AD和其他相关痴呆症(ADRD)影响良好 美国有500多万人。到本世纪中叶，这些数字预计将至少增加两倍。尽管 这种，对于这些毁灭性的疾病没有有效的治疗方法。阿尔茨海默病的发病和进展 与年龄相关的几个关键生理通路的变化有关，包括细胞和线粒体 代谢和基因组稳定性。我们认为这些途径的有效性与年龄有关。 促进AD相关神经退行性变和改善和稳定生理通路的干预 健康寿命的延长将延缓AD的发生和发展。在本提案中，我们将使用 结合苍蝇和小鼠AD模型来确定潜在的遗传学和药理学 已知的可以通过增强活性来延长苍蝇和老鼠的寿命或健康寿命的卵细胞保护剂 细胞和线粒体代谢或基因组稳定性的改善，延缓发病和进展 在小鼠和苍蝇的AD模型中研究神经退行性变和其他与AD相关的表型。这些研究的目标是 是确定新的和新颖的遗传和药理基因保护剂，这些保护剂可以翻译成用于 治疗阿尔茨海默病。 我们将使用特定的分子遗传和药物干预来延长人类的寿命 在苍蝇和小鼠AD的分子遗传模型的背景下，苍蝇或延长小鼠的健康寿命。其效果 将在两个不同的Fly AD模型中评估每种干预的效果(人类A？42的神经元特异性表达 或人类tau)和5XFAD小鼠AD模型。 我们将检验以下假设：(I)已知可以改善细胞和线粒体的基因干预 新陈代谢或基因组稳定性，延长苍蝇的寿命或哺乳动物的健康寿命 可以延缓神经退行性变相关表型的发病和进展的雌激素保护剂 苍蝇和小鼠AD模型以及(Ii)已知可改善细胞和线粒体的药物干预 新陈代谢或基因组的稳定性和延长苍蝇的寿命或哺乳动物的健康寿命可以推迟发病和 苍蝇和小鼠AD模型中神经退行性变相关表型的进展。 我们将确定这些干预措施是否延缓了一系列AD相关疾病的发生和进展 神经退行性变的表型包括：(I)整体机体健康下降(苍蝇的寿命，小鼠的虚弱)； (2)丧失神经行为的稳健性或恢复力(苍蝇的活动性和昼夜节律，一系列 小鼠的神经行为测试)；(Iii)脑神经变性的显微组织学检查 苍蝇视网膜和小鼠相关区域的大体和显微神经病理学检查 以及(Iv)小鼠的分子变化。

Project Summary/Abstract: (30 lines maximum) The overall goal of this proposal is to develop genetic and pharmacological interventions that will delay the onset and progression of Alzheimer’s Disease (AD). AD and other Related Dementias (ADRD) affect well over 5 million people in the United States. By mid-century, these numbers are predicted to at least triple. Despite this, there are no effective treatments for these devastating illnesses. The onset and progression of AD has been linked to age-related changes in several critical physiological pathways including cellular and mitochondrial metabolism and genomic stability. We propose the age-related decline in the efficacy of these pathways promotes AD-related neurodegeneration and interventions which improve and stabilize physiological pathways leading to extension of healthy life span will delay the onset and progression of AD. In this proposal we will use the fly and mouse AD models in combination to determine whether potential genetic and pharmacological geroprotectors known to extend life span or health span in flies and mice, through an enhancement of the activity of cellular and mitochondrial metabolism or improvement in genomic stability, delay the onset and progression of neurodegeneration and other AD-related phenotypes in AD models in mice and flies. The goal of these studies is to identify new and novel genetic and pharmacological geroprotectors that can be translated for use in the treatment of AD. We will use specific molecular genetic and pharmacological interventions known to extend life span in flies or to extend health span in mice in the context of molecular genetic models of fly and mouse AD. The effect of each intervention will be evaluated in two different fly AD models (neuronal-specific expression of human Aß42 or human tau) and the 5XFAD mouse AD model. We will test the hypotheses that: (i) genetic interventions known to improve cellular and mitochondrial metabolism or genomic stability and to extend life span in flies or health span in mammals serve as geroprotectors that can delay the onset and progression of the neurodegeneration associated phenotypes in the fly and mouse models of AD and (ii) pharmacological interventions known to improve cellular and mitochondrial metabolism or genomic stability and extend life span in flies or health span in mammals can delay the onset and progression of the neurodegeneration associated phenotypes in the fly and mouse AD models. We will determine whether these interventions delay the onset and progression of a series of AD-related neurodegeneration phenotypes including: (i) decline in whole organismal health (life span in flies, frailty in mice); (ii) loss of neurobehavioral robustness or resilience (mobility and circadian rhythms in flies, a series of neurobehavioral tests in mice); (iii) microscopic histological examination of neurodegeneration in the brain and the retina of flies and gross and microscopic neuro-pathological examination of the relevant regions of the mouse brain; and (iv) molecular changes in mice.