Synergistic patterned neurodegeneration by APP and APOE4

APP 和 APOE4 的协同模式神经变性

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease model Alzheimer&apos 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

项目摘要

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.

项目概要阿尔茨海默病 (AD) 是导致痴呆症的最常见原因，也是人类第六大死因美国，但 AD 的确切病因尚不清楚。一些 AD 病例显然与淀粉样蛋白有关前体蛋白（APP）基因，编码分解成有毒肽和肽的蛋白质形成斑块的聚集体。然而，大多数 AD 病例与 apolipid 的特定变体有关 E(APOE)基因；超过 40% 的 AD 患者携带 APOE4，而携带两个 APOE4 等位基因的人一生中患 AD 的风险超过 90%。尽管 APP 已经接受了多项深入研究几十年来，人们仍然不确定 APP 如何导致模式性神经变性，以及如何 APOE4与APP协同为AD做出贡献。小鼠模型取得重要进展广告；然而，这些方法通常受到小鼠表现所需两年的限制退化。为了加快发现速度，Pierce-Shimomura 实验室最近开发了一种新颖的 APP 相关使用线虫秀丽隐杆线虫的神经变性模型。该模型表达了人类APP泛有趣的是，随着蠕虫在体内的年龄增长，特定神经元子集的退化只有一周。这种模式化的神经变性模仿了人类 AD 的一个重要特征神经变性优先影响相关大脑区域的某些胆碱能神经元有记忆。该模型还模仿了人类 AD 的一个重要方面，即 APP 诱导的表达 APOE4 会加速神经变性，但表达 APOE3 则不会。使用细胞特异性蛋白质组学以及秀丽隐杆线虫中与 APP 相关的神经变性模型，他们的目的是阐明分子机制 AD 模式性神经变性的基础。他们的方法解决了 AD 中的两个关键问题研究：为什么特定神经元会死亡？ APOE4 如何增加神经退行性变的风险？最后，如何靶向一种新的配体，即 sigma 2 受体，该受体在蠕虫和人类中保守，具有小分子缓解神经退行性变？从线虫 APP 模型研究中获得的知识可以然后用于产生新的假设，并在 AD 哺乳动物模型中进行测试，并可能导致治疗 AD 的新疗法。