Alzheimer’s Disease Protection by Reduced Adenylyl Cyclase Type 5

项目概要： 阿尔茨海默氏病（AD）与代谢功能障碍、葡萄糖和胰岛素抵抗、氧化应激、高脂血症和高脂血症有关。 压力、线粒体功能障碍和运动能力降低。氧化应激与线粒体功能障碍 与β-淀粉样蛋白（Aβ）沉积的发展相关，A β沉积是AD的标志之一， 记忆力和认知能力的下降此外，AD患者的寿命缩短。因此 将有益于研究具有增强的代谢、葡萄糖和胰岛素的健康长寿的新模型。 胰岛素耐受性、运动能力和抗氧化应激、线粒体功能障碍，以及 凋亡所有这些特征都存在于腺苷酸环化酶5型（AC 5）敲除（KO）小鼠中， 表现出健康长寿，与所有主要的分子因素，防止AD。腺苷酸环化酶 (AC)诱导环磷酸腺苷（cAMP），因此，调节交感神经控制和β-肾上腺素能受体（β- AR）信号，因此是从酵母到哺乳动物的生物体中健康和长寿的关键调节因子。 AC 5是十种AC亚型之一，几乎在身体的每个器官中表达，包括大脑。在 为了支持其在衰老中作用，我们发现AC 5的破坏（AC 5 KO）促进健康长寿， 增强运动表现，预防糖尿病和心力衰竭，所有这些都应该是有益的 预防AD。我们的初步数据还表明，AC 5 KO小鼠在记忆和运动方面表现更好， 与野生型小鼠相比。相反，阿尔茨海默病模型J20小鼠，一种转基因动物， 过表达突变的人淀粉样前体蛋白（APP），表现出预期的记忆丧失。我们 假设AC 5 KO小鼠和脑特异性AC 5 KO小鼠（AC 5 BKO）是保护模型 并且缺乏AC 5的J20小鼠将被保护免于淀粉样蛋白Aβ相关的病理。第一特定 目的将确定AC 5是否在AD相关病理学中发挥作用，以及删除它是否减轻J20 表型第二个具体目标将确定AC 5 KO小鼠的增强性能是否 由于其系统作用或在脑中选择性缺失AC 5是否足以具有有益效果 AD样表型。重要的是，我们可以使用解决这些问题所需的所有鼠标线， study.

Project Summary: Alzheimer’s Disease (AD) is associated with metabolic dysfunction, glucose and insulin resistance, oxidative stress, mitochondrial dysfunction, and reduced exercise capacity. Oxidative stress and mitochondrial dysfunction correlate with the development of beta-amyloid (Aβ) deposits, one of the hallmarks of AD that begin years before the onset of memory and cognitive decline. Moreover, patients with AD have a reduced lifespan. Accordingly, it would be beneficial to examine novel models of healthful longevity with enhanced metabolism, glucose and insulin tolerance, exercise capacity, and protection against oxidative stress, mitochondrial dysfunction, and apoptosis. All these features are present in the adenylyl cyclase type 5 (AC5) knock out (KO) mouse, which exhibits healthful longevity, associated with all major molecular factors that protect against AD. Adenylyl cyclase (AC) induces cyclic AMP (cAMP) and, therefore, regulates sympathetic control and β-adrenergic receptor (β- AR) signaling, and is thus a key regulator of health and longevity in organisms ranging from yeast to mammals. AC5 is one of ten AC isoforms and is expressed in virtually every organ in the body, including the brain. In support of its role in aging, we have found that disruption of AC5 (AC5 KO) promotes healthful longevity, enhances exercise performance and protects against diabetes and heart failure, all of which should be helpful in protecting against AD. Our preliminary data also show that AC5 KO mice perform better on memory and motor tasks compared to wild-type mice. In contrast, the Alzheimer model J20 mice, a transgenic animal that overexpresses mutant human amyloid precursor protein (APP), exhibits memory loss as expected. We hypothesize that the AC5 KO mouse and the brain-specific AC5 KO mice (AC5 BKO) are models for protection against AD and that J20 mice lacking AC5 will be protected from amyloid Aβ related pathology. The first specific aim will determine whether AC5 plays a role in AD-related pathology and whether deleting it mitigates the J20 phenotype. And the second specific aim will determine whether the enhanced performance of AC5 KO mice is due to its systemic actions or whether selective deletion of AC5 in the brain is sufficient to have a beneficial effect on AD-like phenotype. Importantly, all mouse lines needed to address these questions are available to us for study.