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：
10195947
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 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10195947
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 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.

痴呆症是一种进行性、无法治愈且致命的神经退行性疾病。疾病（AD）是进行性痴呆的主要原因，其次是路易体痴呆和额颞叶痴呆 (FTD) 的患病率随着年龄的增长而增加。随着全球寿命的延长，ADRD 的社会影响将变得更加严重。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) 的积累以及受影响组织内和周围的 tau 蛋白，导致神经元细胞死亡。可以缓解一些 ADRD 症状，但目前针对 ADRD 的治疗干预措施还不够，有人认为，它们无法通过改善潜在的病理学来改变疾病的进展。发现一种可以预防或逆转 α-syn、Aβ 和 tau 蛋白等神经毒性形式的分子寡聚物和原纤维可以减缓或逆转 ADRD 疾病。我们最近发现了 Fas 细胞凋亡抑制分子 (FAIM)，它可以预防和逆转体外致病性 α-syn、Aβ 和 tau 物种，表明 FAIM 可能在拮抗中发挥关键作用此外，据报道，FAIM 的表达在体内降低。 AD 患者的海马样本，特别是在 BRAAK 晚期阶段，进一步表明尽管有关于 FAIM 体外活性和 AD 脑中低 FAIM 表达的令人信服的数据，但无论是 FAIM 在多大程度上参与预防/清除神经元中的神经毒性蛋白，以及调节神经元中 FAIM 表达的因素仍未被探索。这项研究的长期目标是更好地理解基本分子机制 ADRD 中的 FAIM 功能/表达，可能有助于开发新的预防或疾病缓解药物消除 ADRD 患者神经毒性 α-syn、Aβ 和 tau 物质以减缓或逆转 ADRD 的策略具体来说，该提案的直接目标是确定调节 FAIM 的因素。我们将在源自人类诱导多能干细胞 (iPSC) 的皮质神经元中进行表达。进一步确定 FAIM 缺乏或 FAIM 过度表达是否以及在多大程度上影响使用 FAIM 缺陷或 FAIM 过度表达的皮质神经元来检测致病性 tau 物种的水平。拟议的研究将首次确定 FAIM 表达水平是否与 ADRD 相关除了分子机制外，还通过改变致病蛋白种类的形成来调节致病机制人类 FAIM 基因在神经元中的调控机制有可能增加一个新的层面。了解 ADRD 发病和进展的病理生理学，这可能与 FAIM 相关这将为 FAIM 表达之间的相互关系提供新的见解。及其调节因子、蛋白质寡聚化/原纤维化以及 ADRD 发病机制。