The involvement of Adapt78 in Alzheimer's disease and Down Syndrome

描述（由申请人提供）：ADAPT 78（RCAN 1）是哺乳动物细胞中的应激诱导基因。它产生一种结合并抑制细胞内钙调神经磷酸酶的蛋白质（Adapt 78），钙调神经磷酸酶是一种介导许多脑细胞对钙反应的磷酸酶。在过去的几年中，提示性证据已经积累支持异常ADAPT 78表达在神经疾病中的可能参与。重要的是，在阿尔茨海默病和唐氏综合征中均观察到大脑中Adapt 78的过表达，并且果蝇神经元中Adapt 78同源物的过表达导致显著的认知障碍。该假说认为Adapt 78过度表达导致阿尔茨海默氏症和唐氏综合征患者中观察到的加速痴呆。这将通过使用在神经元中过表达人ADAPT 78的新产生的转基因小鼠来测试，以确定神经元Adapt 78过表达是否随时间推移导致认知障碍。此外，转基因小鼠将用于确定Adapt 78神经元过表达是否改变被认为在学习和记忆中重要的蛋白质的水平和活性，包括钙调神经磷酸酶调节的tau，NFAT和CREB以及MAP激酶和PKA。还将在形态学上评价神经变性、细胞凋亡、神经胶质增生和Adapt 78聚集体形成。结合起来，希望这些研究将支持ADAPT 78（RCAN 1）在阿尔茨海默病中的作用，包括唐氏综合征的加速痴呆特征。公共卫生相关性：最近的证据表明，Adapt 78，这个提议的主题，涉及阿尔茨海默氏病和唐氏综合症中观察到的早发性痴呆。阿尔茨海默病是所有神经退行性疾病中最常见的一种，据信有多达450万美国人患有这种疾病，其中包括近一半的85岁及以上的人。唐氏综合症影响1/800的人类，是最普遍的基于遗传的智力迟钝的原因。我们提出的研究，如果成功的话，可能会提供新的见解阿尔茨海默氏症和唐氏症患者的早发性痴呆症，并确定一个新的基因/蛋白质，可以有针对性地治疗这些疾病。因此，拟议的主题事项与健康有重大关系。

DESCRIPTION (provided by applicant): ADAPT78 (RCAN1) is a stress-inducible gene in mammalian cells. It produces a protein (Adapt78) that binds to and inhibits intracellular calcineurin, a phosphatase that mediates many brain cellular responses to calcium. Over the last several years, suggestive evidence has accrued supporting the possible involvement of aberrant ADAPT78 expression in neural disorders. Importantly, overexpression of Adapt78 in brain is observed in both Alzheimer's disease and Down syndrome, and overexpression of an Adapt78 homolog in Drosophila neurons leads to dramatic cognitive impairment. The hypothesis is that Adapt78 overexpression contributes to Alzheimer's and the accelerated dementia observed in Down syndrome patients. This will be tested by using newly generated transgenic mice overexpressing human ADAPT78 in neurons to determine whether neuronal Adapt78 overexpression leads to cognitive impairment over time. In addition, the transgenic mice will be used to determine whether Adapt78 neuronal overexpression alters the levels and activities of proteins thought to be important in learning and memory, including calcineurin-regulated tau, NFAT and CREB as well as MAP kinases and PKA. Morphologically, neurodegeneration, apoptosis, gliosis and Adapt78 aggregate formation will also be evaluated. Combined, it is hoped that these studies will support a role for ADAPT78 (RCAN1) in Alzheimer's disease including the accelerated dementia characteristic of Down syndrome. PUBLIC HEALTH RELEVANCE: Recent evidence suggests that Adapt78, the subject of this proposal, is involved in Alzheimer's disease and the early onset dementia observed in Down syndrome. Alzheimer's disease is the most common of all neurodegenerative disorders, with up to 4.5 million Americans thought to suffer from it, including nearly half of those 85 years of age and older. Down syndrome affects 1 in 800 humans and is the most prevalent genetic-based cause of mental retardation. Our proposed studies, if successful, may provide new insight into Alzheimer's and early onset dementia in Down's patients, and identify a new gene/protein that can be targeted to potentially treat these disorders. Thus, the proposed subject matter has major health relevance.