The intersection of Alzheimer’s disease and ribosome biogenesis through Amyloid Beta Precursor Protein Binding Family B Member 1 (APBB1; FE65)

阿尔茨海默病(AD)是一种神经退行性疾病，其特征是认知能力下降和 失忆。它影响了大约550万美国人，是全球第六大致病原因 美国的死亡案例。淀粉样蛋白级联假说，由蛋白质分解过程引起的 淀粉样前体蛋白(APP)是AD病因的主要建议之一；然而， 针对淀粉样β蛋白(Aβ)斑块形成的药物在临床试验中失败。未能做到 生产一种治疗阿尔茨海默病的根本原因而不是症状的药物，表明在 我们对这种疾病的发病机制的理解。而APP是最引人注目的先驱 致病过程也会产生与β有关的细胞内肽(AICD) 聚合酶II与接头蛋白淀粉样β前体蛋白结合家族的转录 B成员1(APBB1；FE65)。在这里，我提供了初步数据，支持APBB1在 对制造核糖体的基本过程的调节。此外，核糖体生物发生具有 与神经元的生长和存活有关，而这一过程中的功能障碍 在阿尔茨海默病患者死后脑内观察到。这些观察结果导致一些人提出了一种联系 核糖体生物发生与阿尔茨海默病发病机制之间的关系，本提案将探讨这一联系 通过APBB1。首先，我建议探讨APBB1调节核糖体生物发生的机制 在细胞培养系统中(特定目标1)。第二，我建议测试APBB1的程度 调节原代小鼠神经元核糖体的生物发生，并有助于神经元的可塑性和 生存能力(特定目标2)。我假设APBB1以一种AICD依赖的方式调节 核糖体生物发生作为核仁基因转录的辅助因子 核糖体生物发生。我还假设APBB1是正常神经解剖学所必需的，包括 树突和树突的密度和形态。最后，我假设因为APBB1的S 在核糖体生物发生中的作用，其枯竭会触发核仁应激反应，导致 P53的稳定与细胞凋亡。这一提议将拓宽我们对核糖体的理解 神经元中的生物发生，也有助于深入了解核糖体生物发生和 AD，为药物发现开辟了新的潜在途径。

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by cognitive decline and memory loss. It affects approximately 5.5 million Americans, and is the sixth-leading cause of death in the United States. The amyloid cascade hypothesis, caused by proteolytic processing of the amyloid precursor protein (APP), is one of the leading proposals for the cause of AD; however, drugs that target amyloid beta (Aβ) plaque formation have failed in clinical trials. The failure to produce a drug that treats the underlying cause of AD rather than its symptoms, suggests a gap in our understanding of the pathogenesis of this disease. While APP is most notable as the precursor of Aβ, pathogenic processing also produces an intracellular peptide (AICD) implicated in RNA polymerase II transcription with the adaptor protein Amyloid Beta Precursor Protein Binding Family B Member 1 (APBB1; FE65). Here, I present preliminary data that supports a novel role for APBB1 in the regulation of the essential process of making ribosomes. Furthermore, ribosome biogenesis has been associated with neuronal growth and viability, and dysfunction in this process has been observed in post-mortem AD patient brains. These observations have led some to propose a link between ribosome biogenesis and the pathogenesis of AD, and this proposal will explore this link through APBB1. First, I propose to probe the mechanism by which APBB1 regulates ribosome biogenesis in a cell culture system (Specific Aim 1). Second, I propose to test the extent to which APBB1 regulates ribosome biogenesis in primary mouse neurons, and contributes to neuronal plasticity and viability (Specific Aim 2). I hypothesize that APBB1, in an AICD-dependent manner, regulates ribosome biogenesis as a cofactor for the transcription of nucleolar genes that are required for ribosome biogenesis. I also hypothesize that APBB1 is required for normal neuroanatomy including dendrite and dendritic spine density and morphology. Finally, I hypothesize that because of APBB1’s role in ribosome biogenesis, its depletion will trigger the nucleolar stress response leading to p53 stabilization and apoptosis. This proposal will both broaden our understanding of ribosome biogenesis in neurons, and also lend insight into the intersection between ribosome biogenesis and AD, opening new potential avenues for drug discovery.