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

Adapt78 与阿尔茨海默病和唐氏综合症的关系

• 批准号: 8018853
• 负责人: DANA R CRAWFORD
• 金额: $ 2.83万
• 依托单位: ALBANY MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8018853
• 关键词: Affect; Age; Age-Years; Alzheimer' s Disease; American; Apoptosis; Behavioral; Binding; Biochemical; Brain; CREB1 gene; Calcineurin; Calcium; Cells; Characteristics; Chromosome Mapping; Chromosomes, Human, Pair 21; Cognition; Cyclic AMP-Dependent Protein Kinases; DSCR1 protein; Dementia; Disease; Down Syndrome; Drosophila genus; Gene Proteins; Genes; Genetic; Gliosis; Health; Hippocampus (Brain); Homologous Gene; Human; Human Chromosomes; Impaired cognition; Learning; Long-Term Depression; Long-Term Potentiation; Longevity; Mammalian Cell; Mediating; Memory; Mental Retardation; Mitogen-Activated Protein Kinases; Mus; Nerve Degeneration; Neurites; Neurodegenerative Disorders; Neuron-Specific Enolase; Neurons; Orthologous Gene; Patients; Phosphoric Monoester Hydrolases; Presenile Alzheimer Dementia; Proteins; Risk Factors; Role; Signal Transduction; Stress; Testing; Time; Transgenic Mice; adapt78; base; early onset; in vivo Model; insight; neuron apoptosis; neurotransmitter release; novel; overexpression; promoter; public health relevance; relating to nervous system; response; tau Proteins

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.

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。它产生一种蛋白质 (Adapt78)，该蛋白质结合并抑制细胞内钙调神经磷酸酶，这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，越来越多的暗示性证据支持异常的 ADAPT78 表达可能与神经疾病有关。重要的是，在阿尔茨海默病和唐氏综合症中都观察到了大脑中Adapt78的过度表达，而果蝇神经元中Adapt78同源物的过度表达会导致严重的认知障碍。该假设认为，Adapt78 过度表达会导致阿尔茨海默氏症和唐氏综合症患者中观察到的加速痴呆症。这将通过使用新产生的在神经元中过度表达人类 ADAPT78 的转基因小鼠进行测试，以确定神经元 Adapt78 过度表达是否会随着时间的推移导致认知障碍。此外，转基因小鼠将用于确定Adapt78神经元过度表达是否会改变被认为对学习和记忆很重要的蛋白质的水平和活性，包括钙调磷酸酶调节的tau蛋白、NFAT和CREB以及MAP激酶和PKA。在形态学上，还将评估神经变性、细胞凋亡、神经胶质增生和 Adapt78 聚集体形成。综合而言，希望这些研究能够支持 ADAPT78 (RCAN1) 在阿尔茨海默病（包括唐氏综合症的加速痴呆特征）中的作用。公共健康相关性：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症中观察到的早发性痴呆有关。阿尔茨海默氏病是所有神经退行性疾病中最常见的一种，据信有多达 450 万美国人患有该病，其中近一半是 85 岁及以上的老年人。唐氏综合症影响每 800 人中就有 1 人，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，并确定可以靶向治疗这些疾病的新基因/蛋白质。因此，所提议的主题具有重大的健康相关性。