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

描述(申请人提供)：ADAPT78(RCAN1)是哺乳动物细胞中的应激诱导基因。它产生一种蛋白质(Adapt78)，与细胞内钙调神经磷酸酶结合并抑制，钙调神经磷酸酶介导许多脑细胞对钙的反应。在过去的几年中，已经积累了支持ADAPT78异常表达可能参与神经障碍的提示性证据。重要的是，在阿尔茨海默病和唐氏综合症患者的大脑中都观察到了Adapt78的过度表达，而在果蝇神经元中Adapt78同源基因的过度表达会导致严重的认知障碍。假设Adapt78的过度表达导致了在唐氏综合症患者中观察到的阿尔茨海默病和加速痴呆症。这将通过使用新产生的在神经元中过度表达人ADAPT78的转基因小鼠来测试，以确定随着时间的推移，神经元Adapt78过度表达是否会导致认知障碍。此外，转基因小鼠将被用来确定Adapt78神经元的过度表达是否改变了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。在形态上，还将评估神经退行性变、细胞凋亡、胶质增生和Adapt78聚集体形成。总而言之，希望这些研究将支持ADAPT78(RCAN1)在阿尔茨海默病包括唐氏综合症特征的加速痴呆症中的作用。公共卫生相关性：最近的证据表明，这项提案的主题Adapt78与阿尔茨海默病和唐氏综合症中观察到的早发性痴呆症有关。阿尔茨海默氏症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这种疾病，其中包括近一半85岁及以上的人。每800人中就有1人患有唐氏综合症，这是导致智力低下的最常见的遗传原因。我们提出的研究如果成功，可能会为唐氏症患者的阿尔茨海默氏症和早发性痴呆症提供新的洞察力，并确定一种新的基因/蛋白质，可以作为潜在的靶向治疗这些疾病。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.