Synergistic patterned neurodegeneration by APP and APOE4

APP 和 APOE4 的协同模式神经变性

• 批准号: 9414391
• 负责人: JONATHAN THOMAS PIERCE
• 金额: $ 192.49万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9414391
• 关键词: Address; Adult; Aftercare; Age; Alleles; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease risk; Amino Acids; Amyloid beta-Protein Precursor; Brain region; Caenorhabditis elegans; Cause of Death; Cells; Cognitive deficits; Collection; Dementia; Down Syndrome; Drug Targeting; Ectopic Expression; Etiology; Exhibits; Gene Proteins; Genes; Genetic Population Study; Human; Human Amyloid Precursor Protein; Individual; Knowledge; Label; Lead; Life; Ligands; Light; Link; Mass Spectrum Analysis; Mediating; Memory; Modeling; Molecular; Mus; Mutation; Nematoda; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Pathway interactions; Patients; Pattern; Peptides; Pharmaceutical Preparations; Preclinical Drug Evaluation; Prevention; Process; Proteins; Proteomics; RNA Interference; Research; Resistance; Risk; Risk Factors; Rodent Model; Speed; System; Testing; Time; Variant; Work; age related; amyloid precursor protein processing; cholinergic neuron; cognitive performance; early onset; in vivo; in vivo Model; insight; killings; middle age; mouse model; mutant; neuroprotection; novel; novel therapeutics; prevent; sigma-2 receptor; small molecule; therapeutic target

PROJECT SUMMARY Alzheimer disease (AD) is the most common cause of dementia and the 6th leading cause of death in the US, but the precise etiology of AD is unclear. Some cases of AD are clearly linked to the amyloid precursor protein (APP) gene which encodes a protein that is broken into toxic peptides and peptide aggregates that form plaques. Most cases of AD, however, are linked to a specific variant of the apolipid E (APOE) gene; over 40% of people with AD carry APOE4 and those who carry two APOE4 alleles have greater than 90% life-time risk of developing AD. Although APP has received intense study over several decades, it remains uncertain how APP leads to patterned neurodegeneration, and moreover how APOE4 synergizes with APP to contribute to AD. Important progress is being made with mouse models of AD; however, these approaches are often limited by the two years required for mice to display degeneration. To speed discovery, the Pierce-Shimomura lab recently developed a novel APP-related neurodegeneration model using the nematode C. elegans. The model expresses human APP pan- neuronally and intriguingly displays degeneration of specific subsets of neurons as the worm ages within only one week. This patterned neurodegeneration mimics an important hallmark of AD in humans in which neurodegeneration preferentially effects certain cholinergic neurons in brain regions associated with memory. The model also mimics an important aspect of human AD in that APP-induced neurodegeneration is accelerated by expressing APOE4, but not APOE3. Using cell-specific proteomics and the model of APP-related neurodegeneration in C. elegans, they aim to shed light on the molecular basis of patterned neurodegeneration in AD. Their approach addresses two critical questions in AD research: Why do specific neurons die? How does APOE4 increase risk of neurodegeneration? Finally, how does targeting a novel ligand, the sigma 2 receptor, conserved in worms and humans with small molecules relieve neurodegeneration? Knowledge gained from study in the C. elegans APP model can then be used to generate novel hypotheses to be tested in mammalian models of AD and may lead to novel therapeutics to treat AD.

项目总结 阿尔茨海默病(AD)是导致痴呆症的最常见原因，也是全世界第六大致死原因 美国，但AD的确切病因尚不清楚。一些阿尔茨海默病病例显然与淀粉样蛋白有关 前体蛋白(APP)基因，编码一种蛋白质，该蛋白质被分解成有毒的多肽和多肽 形成斑块的聚集体。然而，大多数AD病例与特定的载脂蛋白变体有关 E(APOE)基因；超过40%的AD患者携带APOE4，携带两个APOE4等位基因的人 患阿尔茨海默病的终生风险超过90%。尽管APP在几个问题上得到了密集的研究 几十年来，APP是如何导致模式神经变性的，而且是如何导致的，仍然不确定 ApoE4与APP协同作用为AD做出贡献。老鼠模型的研究正在取得重要进展 阿尔茨海默病；然而，这些方法通常受到老鼠表现所需的两年的限制 退化。为了加快发现速度，皮尔斯-下村实验室最近开发了一款与 使用线虫线虫的神经退化模型。该模型表达了人类应用程序的泛- 当蠕虫在体内老化时，神经性的和耐人寻味的显示特定神经元亚群的退化 只有一周。这种有模式的神经退行性变模仿了人类AD的一个重要标志 哪种神经退行性变优先影响相关脑区的某些胆碱能神经元 带着记忆。该模型还模拟了人类AD的一个重要方面，即APP诱导的 神经退行性变通过表达APOE4而不是APOE3来加速。使用细胞特异性蛋白质组学 以及线虫APP相关神经退化的模型，他们的目标是阐明分子 阿尔茨海默病模型神经退行性变的基础。他们的方法解决了AD中的两个关键问题 研究：为什么特定的神经元会死亡？载脂蛋白4如何增加神经退行性变的风险？最后， 靶向一种新的配体，Sigma 2受体，如何在蠕虫和人类中保守 分子能缓解神经退化吗？通过研究线虫APP模型获得的知识可以 然后被用来产生新的假说，以在AD的哺乳动物模型中进行测试，并可能导致 治疗AD的新疗法。