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）是一种以认知能力下降为特征的神经退行性疾病， 失忆它影响了大约550万美国人，是第六大原因， 死亡在美国。淀粉样蛋白级联假说，由蛋白质的蛋白水解加工引起， 淀粉样前体蛋白（APP）是AD病因的主要建议之一;然而， 针对淀粉样蛋白β（Aβ）斑块形成的药物在临床试验中失败。未能 生产一种药物，治疗AD的根本原因，而不是其症状，这表明， 我们对这种疾病的发病机制的理解 疾病虽然APP是最值得注意的先驱， Aβ的致病性加工也产生与RNA有关的细胞内肽（AICD）， 聚合酶II转录与衔接蛋白淀粉样β前体蛋白结合家族 B成员1（APBB 1; FE 65）。在这里，我提出了初步的数据，支持APBB 1的一个新的作用， 对核糖体形成的基本过程的调节。此外，核糖体生物合成具有 与神经元的生长和活力有关，而在这一过程中的功能障碍已经被发现。 在AD患者死后的大脑中观察到。这些观察使一些人提出了一种联系， 核糖体生物合成与AD发病机制之间的联系，本提案将探讨这一联系 通过APBB 1。首先，我建议探索APBB 1调节核糖体生物合成的机制 在细胞培养系统中（具体目标1）。第二，我建议测试APBB 1 调节原代小鼠神经元中的核糖体生物发生，并有助于神经元的可塑性， 具体目标2（Specific Aim 2）我假设APBB 1以AICD依赖的方式调节 核糖体生物合成作为核仁基因转录的辅助因子， 核糖体生物发生我还假设APBB 1是正常神经解剖学所必需的， 树突和树突棘密度和形态。最后，我假设由于APBB 1的 在核糖体生物合成中的作用，其消耗将触发核仁应激反应，导致 p53稳定和凋亡。这一建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.