Alzheimer’s Disease Protection by Reduced Adenylyl Cyclase Type 5

项目总结： 阿尔茨海默病(AD)与代谢功能障碍、葡萄糖和胰岛素抵抗、氧化 压力、线粒体功能障碍和运动能力下降。氧化应激与线粒体功能障碍 与β-淀粉样蛋白(A-β)沉积的发展有关，这是早在几年前就开始的AD的特征之一 记忆力和认知能力衰退的开始。此外，阿尔茨海默病患者的寿命会缩短。因此，它 将有益于研究新的健康长寿模型，通过增强新陈代谢、葡萄糖和 胰岛素耐量、运动能力和对氧化应激、线粒体功能障碍的保护，以及 细胞凋亡。所有这些特征都存在于腺酰环化酶5(AC5)基因敲除(KO)小鼠中，该小鼠 表现出健康的长寿，与所有预防AD的主要分子因素有关。腺酰环化酶 (Ac)诱导环磷酸腺苷(CAMP)，从而调节交感神经控制和β肾上腺素能受体(β- AR)信号，因此在从酵母到哺乳动物的各种生物中，它是健康和长寿的关键调节因子。 AC5是十种AC亚型之一，几乎在身体的每个器官中都有表达，包括大脑。在……里面 支持其在衰老中的作用，我们发现AC5(AC5 KO)的破坏促进了健康长寿， 提高运动能力，预防糖尿病和心力衰竭，所有这些都应该是有帮助的 在预防AD方面。我们的初步数据还表明，AC5 KO小鼠在记忆和运动方面表现更好 任务与野生型小鼠相比。相比之下，阿尔茨海默病模型J20小鼠是一种转基因动物， 过度表达突变型人淀粉样前体蛋白(APP)，如预期的那样表现出记忆丧失。我们 假设AC5KO小鼠和脑特异性AC5KO小鼠(AC5BKO)为保护模型 而缺乏AC5的J20小鼠将受到保护，免受淀粉样蛋白Aβ相关病理的影响。第一个具体 AIM将确定AC5是否在AD相关病理中发挥作用，以及删除它是否会缓解J20 表型。第二个具体目标将确定AC5KO小鼠的增强性能是否 由于它的全身性作用，或者大脑中AC5的选择性删除是否足以产生有益的效果 关于AD样表型。重要的是，我们提供了解决这些问题所需的所有鼠标行 学习。

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.