Understanding the link between FAIM expression and Alzheimer’s disease and related dementias

了解 FAIM 表达与阿尔茨海默病及相关痴呆症之间的联系

基本信息

批准号：
10380077
负责人：
Hiroaki Kaku
金额：
$ 7.55万
依托单位：
WESTERN MICHIGAN UNIV SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10380077
关键词：
Address Affect Age Alternative Splicing Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease patient Alzheimer&apos s disease related dementia Amino Acids Amyloid beta-Protein Apoptosis Apoptosis Inhibitor Binding Binding Sites Cell Line Cell-Free System Clinical Combined Modality Therapy Comprehension Cultured Cells Data Dementia Deposition Development Disease Disease Progression Etiology Frontotemporal Dementia Functional disorder Future Gene Expression Regulation Genes Genetic Transcription Goals HU Protein Hippocampus (Brain)Human Impairment In Vitro Individual Induced pluripotent stem cell derived neurons Lead Lewy Body Dementia Light Link Longevity Messenger RNA Modeling Molecular Nerve Degeneration Neurodegenerative Disorders Neuroglia Neurons Pathogenesis Pathogenicity Pathologic Pathology Patients Persons Physiological Play Prevalence Prevention Preventive Promoter Regions Proteins RNA Splicing Recombinants Reporting Research Role Sampling Series Symptoms Therapeutic Therapeutic Intervention Time Tissues Transcription Repressor Translations Variant Work alpha synuclein base chromatin immunoprecipitation cohesion high-throughput drug screening humanized antibody in vitro activity in vivo induced pluripotent stem cell insight interest mutant neuron loss neurotoxic overexpression prevent prognostic promoter proteostasis tau Proteins tau aggregation tau mutation transcription factor translational study validation studies

项目摘要

Dementia is a progressive, incurable, and uniformly fatal neurodegenerative disorder. Alzheimer’s disease (AD) is the primary cause of progressive dementia, followed by Lewy body dementia and frontotemporal dementia (FTD). The prevalence of AD and related dementias (ADRD) increases with age. With increasing longevity worldwide, the societal impact of ADRD will become more severe. A common, pathological hallmark of these dementias is the accumulation of abnormal α-synuclein (α-syn), amyloid-β (Aβ) and tau species in and around affected tissues, leading to neuronal cell death. Although treatments are available to relieve some ADRD symptoms, current therapeutic interventions for ADRD are insufficient as they fail to modify disease progression by ameliorating the underlying pathology. It has been suggested that discovery of a molecule that could prevent or reverse neurotoxic forms of α-syn, Aβ and tau species such as oligomers and fibrils could slow or reverse ADRD disease. We recently identified Fas Apoptosis Inhibitory Molecule (FAIM), which can prevent and reverse pathogenic α-syn, Aβ and tau species in vitro, suggesting that FAIM might fulfil a key role in antagonizing these pathogenic species in vivo. Furthermore, it has been reported that FAIM expression is reduced in the hippocampal samples from AD patients, especially in the late BRAAK stages, further suggesting a role in disease. In spite of compelling data on FAIM activity in vitro and of low FAIM expression in AD brain, whether and to what extent FAIM is involved in the prevention/clearance of the neurotoxic proteins in neurons, and what regulates FAIM expression in neurons still remains unexplored. The long-term goal of this study is to gain a greater comprehension of basic molecular mechaisms of FAIM function/expression in ADRD, which may enable development of new preventive or disease-modifying strategies that eliminate neurotoxic α-syn, Aβ and tau species in ADRD patients to slow or reverse ADRD symptoms. Specifically, the immediate goals of this proposal are to identify factors regulating FAIM expression in cortical neurons derived from human induced pluripotent stem cells (iPSCs). We will further determine whether and to what extent FAIM-deficiency or FAIM-overexpression affects the levels of pathogenic tau species using FAIM-deficient or FAIM-overexpressing cortical neurons. The proposed study will determine for the first time whether FAIM expression levels are associated with ADRD pathogenesis through modifying the formation of pathogenic protein species in addition to the molecular mechanism of human FAIM gene regulation in neurons. This work has the potential to add a new layer of understanding in the pathophysiology of ADRD onset and progression, which might be associated with FAIM expression and its regulators. This will provide new insights into the interrelationship among FAIM expression and its regulators, protein oligomerization/fibrillization, and the ADRD pathogenesis.

痴呆是一种进行性，无法治愈且统一致命的神经退行性障碍。阿尔茨海默氏症疾病（AD）是进行性痴呆的主要原因，其次是Lewy身体痴呆和额颞痴呆（FTD）。 AD和相关痴呆症（ADRD）的患病率随着年龄的增长而增加。随着全球寿命的日益增加，ADRD的社会影响将变得更加严重。一个常见这些痴呆症的病理标志是异常α-突触核蛋白（α-Syn），淀粉样蛋白-β（Aβ）的积累和tau物种在受影响的组织中及其周围，导致神经元细胞死亡。虽然治疗是可用于营救某些ADRD症状，目前的ADRD治疗干预措施不足他们无法通过改善潜在的病理来改变疾病进展。有人建议发现可以预防或反向神经毒性形式的α-Syn，Aβ和Tau物种（例如）的分子（例如）低聚物和原纤维可能会减慢或逆转ADRD疾病。我们最近确定了FAS凋亡抑制分子（FAIM），可以预防和逆转在体外，致病性α-Syn，Aβ和Tau物种，表明Faim可能在拮抗作用中扮演关键作用这些病原体在体内。此外，据报道，FAIM表达在来自AD患者的海马样品，尤其是在Braak晚期，进一步表明疾病。尽管在体外和广告大脑中的FAIM表达低的FAIM活动中令人信服，但是否是否 FAIM在多大程度上参与了神经元中神经毒性蛋白的预防/清除，以及调节神经元中FAIM表达的原因仍然是出乎意料的。这项研究的长期目标是对基本分子机制有更深入的理解 ADRD中的FAIM功能/表达，这可能能够开发新的预防或疾病调整消除ADRD患者中神经毒性α-SYN，Aβ和TAU物种的策略，以减慢或反向ADRD 症状。具体而言，该提案的直接目标是确定规范FAIM的因素来自人类诱导多能干细胞（IPSC）的皮质神经元的表达。我们将进一步确定FAIM缺乏或表达的程度是否影响使用FAIM缺乏或过表达的皮质神经元的致病性TAU物种水平。这拟议的研究将首次确定FAIM表达水平是否与ADRD相关通过修饰病原蛋白种类的形成，除了分子外，发病机理人类FAIM基因调节神经元中的机制。这项工作有可能增加一层在ADRD发作和进展的病理生理学中的理解，这可能与FAIM有关表达及其调节剂。这将为FAIM表达之间的相互关系提供新的见解及其调节剂，蛋白质的寡聚/纤维化和ADRD发病机理。