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） 该提案的总体目标是开发遗传和药理干预措施， 阿尔茨海默病（AD）的发病和进展。AD和其他相关痴呆（ADRD）影响良好 超过500万人在美国。到本世纪中叶，这些数字预计将至少增加两倍。尽管 因此，这些毁灭性的疾病没有有效的治疗方法。AD的发病和进展一直是 与年龄相关的变化，在几个关键的生理途径，包括细胞和线粒体 代谢和基因组稳定性。我们提出这些途径的功效与年龄相关的下降 促进AD相关的神经变性和改善和稳定生理通路的干预 从而延长健康寿命将延缓AD的发病和进展。在本提案中，我们将使用 苍蝇和小鼠AD模型的组合，以确定是否潜在的遗传和药理学 已知通过增强活性来延长苍蝇和小鼠的寿命或健康寿命的老年保护剂 细胞和线粒体代谢或基因组稳定性的改善，延迟发病和进展 在小鼠和果蝇的AD模型中，神经退行性变和其他AD相关表型。这些研究的目的 是确定新的和新颖的遗传和药理老年保护剂，可以翻译用于 治疗AD。 我们将使用特定的分子遗传学和药理学干预措施来延长寿命， 苍蝇或延长健康跨度在苍蝇和小鼠AD的分子遗传模型的背景下，在小鼠。效果 将在两种不同的果蝇AD模型（人A β 42的神经元特异性表达）中评价每种干预的效果 或人tau）和5XFAD小鼠AD模型。 我们将测试以下假设：（i）已知的遗传干预可以改善细胞和线粒体 代谢或基因组稳定性以及延长苍蝇的寿命或哺乳动物的健康寿命， 老年保护剂，其可以延迟神经变性相关表型的发作和进展， AD的苍蝇和小鼠模型和（ii）已知改善细胞和线粒体的药理学干预 代谢或基因组稳定性并延长果蝇的寿命或哺乳动物的健康寿命可以延迟发病， 果蝇和小鼠AD模型中神经变性相关表型的进展。 我们将确定这些干预措施是否能延迟一系列AD相关疾病的发作和进展。 神经变性表型包括：（i）整个生物体健康的下降（苍蝇的寿命，小鼠的虚弱）; (ii)神经行为鲁棒性或弹性的丧失（苍蝇的移动性和昼夜节律，一系列 小鼠的神经行为测试）;（iii）脑中神经变性的显微组织学检查， 果蝇视网膜和小鼠相关区域的大体和显微镜神经病理学检查 脑;和（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.