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

痴呆症是一种进行性、不可治愈且一致致命的神经退行性疾病。阿尔茨海默 疾病（AD）是进行性痴呆的主要原因，其次是路易体痴呆， 额颞叶痴呆（FTD）。AD和相关痴呆（ADRD）的患病率随年龄增长而增加。 随着全球寿命的延长，ADRD的社会影响将变得更加严重。一个普通的， 这些痴呆的病理标志是异常α-突触核蛋白（α-syn）、淀粉样蛋白-β（Aβ） 和受影响组织中和周围的tau种类，导致神经元细胞死亡。虽然治疗是 可用于缓解一些ADRD症状，目前ADRD的治疗干预不足， 它们不能通过改善潜在的病理改变疾病的进展。有人建议 发现了一种分子，可以预防或逆转α-syn，Aβ和tau种类的神经毒性形式，如 寡聚体和原纤维可以减缓或逆转ADRD疾病。 我们最近发现Fas凋亡抑制分子（FAIM），它可以预防和逆转 在体外的致病性α-syn，Aβ和tau种类，表明FAIM可能在拮抗 这些病原体的种类。此外，据报道，FAIM表达减少， 来自AD患者的海马样品，特别是在BRAAK晚期，进一步表明在 疾病尽管有令人信服的体外FAIM活性和AD脑中FAIM低表达的数据， 以及FAIM在神经元中参与神经毒性蛋白的预防/清除的程度，以及 神经元中FAIM表达的调控机制仍然未被探索。 这项研究的长期目标是更好地理解 FAIM在ADRD中的功能/表达，这可能有助于开发新的预防性或改善疾病的药物。 消除ADRD患者中神经毒性α-syn、Aβ和tau物质以减缓或逆转ADRD的策略 症状具体而言，该提案的近期目标是确定调控FAIM的因素 在源自人诱导多能干细胞（iPSC）的皮质神经元中的表达。我们将 进一步确定FAIM缺陷或FAIM过表达是否以及在多大程度上影响 使用FAIM缺陷或FAIM过表达的皮质神经元测定致病性tau种类的水平。的 这项研究将首次确定FAIM表达水平是否与ADRD相关 致病机制通过修改形成的致病蛋白质种类，除了分子 人FAIM基因在神经元中的调控机制。这项工作有可能增加一个新的层面， 了解ADRD发作和进展的病理生理学，这可能与FAIM相关 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、蛋白质寡聚化/纤维化和ADRD发病机制。

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.