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

描述（由申请人提供）：ADAPT78 （RCAN1）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磷酸酶的蛋白质（Adapt78），钙调磷酸酶是一种磷酸酶，介导许多脑细胞对钙的反应。在过去的几年中，越来越多的证据支持ADAPT78异常表达可能参与神经疾病。重要的是，在阿尔茨海默病和唐氏综合征中都观察到Adapt78在大脑中的过度表达，而在果蝇神经元中过度表达Adapt78同源物会导致严重的认知障碍。假设Adapt78过表达有助于阿尔茨海默氏症和唐氏综合征患者中观察到的加速痴呆。这将通过在神经元中过度表达人类ADAPT78的新产生的转基因小鼠进行测试，以确定神经元过度表达ADAPT78是否会随着时间的推移导致认知障碍。此外，转基因小鼠将被用来确定Adapt78神经元过表达是否会改变学习和记忆中重要蛋白质的水平和活性，包括钙调磷酸酶调节的tau、NFAT和CREB，以及MAP激酶和PKA。形态学方面，神经变性、细胞凋亡、神经胶质瘤和Adapt78聚集体形成也将进行评估。综上所述，希望这些研究能够支持ADAPT78 （RCAN1）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，本提案的主题Adapt78与阿尔茨海默病和唐氏综合征中观察到的早发性痴呆有关。阿尔茨海默病是所有神经退行性疾病中最常见的，多达450万美国人被认为患有此病，其中包括近一半的85岁及以上老人。每800人中就有1人患有唐氏综合症，这是导致智力迟钝的最普遍的遗传原因。我们提出的研究，如果成功，可能会为阿尔茨海默氏症和唐氏症患者的早发性痴呆提供新的见解，并确定一个新的基因/蛋白质，可以潜在地治疗这些疾病。因此，拟议的主题具有重大的健康相关性。

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.