A transcription factor complex specifically induced in neurodegeneration

在阿尔茨海默病中，轴突通常是神经元的第一个受影响的部分。神经退行性刺激 触发导致疾病逆行传播的局部信号通路。我们已经发现它的应用 β-淀粉样蛋白在几分钟内触发轴突内蛋白质的合成，形成独特的转录 因子复合体。这种复合体的形成和功能是诱导神经变性所必需的。 对AD相关肽寡聚体Aβ1-42的反应。这种转录因子复合体出现在 人类死后的脑组织仅限于AD的大脑。在这里，我们建议这个存在 中枢神经系统中的转录因子复合体是年龄相关性神经退行性变的标志 疾病，包括阿尔茨海默氏症。 通过这个方案中的实验，我们将研究疾病特异性转录的相关性 阿尔茨海默病的各种病理表现的因子复合体，我们将研究 基因受其上调或下调。我们将把这些来自阿尔茨海默病大脑的结果与 帕金森病大脑中的发现，以确定通过复合体的信号如何在不同的 神经退行性疾病。利用遗传学和药理学方法，我们将在小鼠身上进行研究 阿尔茨海默病模型是否干扰疾病特异性转录因子复合体 延缓或防止疾病进展。 总而言之，这项研究项目的结果将建立一种新的机制，神经元通过这种机制对 寡聚体Aβ1-42。我们的结果将提供针对这一信号机制的理论基础，并测试 这种方法的可行性。

In Alzheimer’s disease, axons are frequently the first part of a neuron to be affected. Neurodegenerative stimuli trigger local signaling pathways that cause the retrograde spread of disease. We have found that application of beta-amyloid within minutes triggers the intra-axonal synthesis of proteins that form a unique transcription factor complex. The formation and function of this complex is required for the induction of neurodegeneration in response to the AD-related peptide oligomeric Aβ1-42. The appearance of this transcription factor complex in human postmortem brain tissue is restricted to AD brains. Here, we propose that the presence of this transcription factor complex in the central nervous system is a hallmark of age-related neurodegenerative disorders, including Alzheimer’s disease. With the experiments in this proposal we will investigate the relevance of the disease-specific transcription factor complex for the various pathological manifestations of Alzheimer’s disease, and we will study which genes are up- or downregulated by it. We will contrast these results from Alzheimer’s disease brain with findings in Parkinson’s disease brain, to determine how signaling via the complex differs in distinct neurodegenerative disorders. Using genetic and pharmacological approaches, we will investigate in mouse models of Alzheimer’s disease, whether interference with the disease-specific transcription factor complex slows down or prevents disease progression. Together, the results from this research project will establish a novel mechanism by which neurons react to oligomeric Aβ1-42. Our results will provide the rationale for targeting this signaling mechanism and test the feasibility of such an approach.