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: 7662250
• 负责人: DANA R CRAWFORD
• 金额: $ 6.67万
• 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/7662250
• 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）是哺乳动物细胞中应力诱导的基因。它产生一种蛋白质（ADAPT78），该蛋白与细胞内钙调蛋白结合并抑制磷酸酶，该磷酸酶介导许多脑细胞对钙的反应。在过去的几年中，暗示性证据支持了异常ADAPT78表达在神经疾病中的可能参与。重要的是，在阿尔茨海默氏病和唐氏综合症中都观察到Adapt78的过表达，并且在果蝇神经元中的Adapt78同源物的过表达会导致急剧认知障碍。假设是ADAPT78的过表达有助于阿尔茨海默氏症和唐氏综合症患者观察到的加速痴呆症。这将通过使用过表达神经元中人类Adapt78的新生成的转基因小鼠来确定神经元ADAPT78的过表达是否会导致认知障碍。此外，转基因小鼠将用于确定Adapt78神经元的过表达是否会改变被认为在学习和记忆中很重要的蛋白质的水平和活性，包括钙调蛋白调节的TAU，NFAT和CREB以及MAP激酶和PKA。在形态上，还将评估神经退行性，凋亡，神经胶质病和Adapt78骨料形成。结合在一起，希望这些研究能够支持ADAPT78（RCAN1）在阿尔茨海默氏病中的作用，包括唐氏综合症的加速痴呆特征。公共卫生相关性：最近的证据表明，该提案的主题Adapt78参与了阿尔茨海默氏病和唐氏综合症中观察到的早期发作痴呆症。阿尔茨海默氏病是所有神经退行性疾病中最常见的，最多450万美国人被认为患有疾病，其中包括85岁及以上的近一半。唐氏综合症会影响800人中的1人，是最普遍的基于遗传的智力障碍原因。我们提出的研究（如果成功）可能会提供有关Down患者中阿尔茨海默氏症和早期发作痴呆症的新见解，并确定可以针对潜在治疗这些疾病的新基因/蛋白质。因此，拟议的主题具有重要的健康相关性。