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

阿尔茨海默病和核糖体生物发生通过淀粉样β前体蛋白结合家族 B 成员 1 (APBB1; FE65) 的交叉

• 批准号: 9469760
• 负责人: Lisa Ogawa McLean
• 金额: $ 4.4万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-01 至 2020-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9469760
• 关键词: Adaptor Signaling Protein; Affect; Alpha Cell; Alzheimer' s Disease; American; Amyloid; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Animal Model; Apoptosis; Autopsy; Binding Proteins; Biochemical Genetics; Biogenesis; Biological Assay; Biological Models; Brain; Breast; Candidate Disease Gene; Caspase; Cause of Death; Cell Compartmentation; Cell Culture System; Cell Culture Techniques; Cell Line; Cell Nucleolus; Cells; Clinical Trials; Confocal Microscopy; Critical Thinking; Data; Defect; Dendritic Spines; Development; Disease; Drug Targeting; Educational process of instructing; Epithelial; Failure; Family; Functional disorder; Genes; Genetic Techniques; Genetic Transcription; Goals; Human; Impaired cognition; Link; Luciferases; MCF10A cells; Memory Loss; Morphology; Mus; Neuraxis; Neuroanatomy; Neurodegenerative Disorders; Neuronal Plasticity; Neurons; Northern Blotting; Nuclear; Nucleolar Proteins; Pathogenesis; Pathogenicity; Patients; Peptides; Pharmaceutical Preparations; Play; Process; Protein Precursors; Proteins; Proteolytic Processing; RNA Polymerase II; RNA analysis; Regulation; Reporting; Research; Ribosomal DNA; Ribosomal RNA; Ribosomes; Role; Scientist; Small Interfering RNA; Symptoms; TP53 gene; Testing; Training; Transcriptional Regulation; United States; Western Blotting; Writing; abeta accumulation; aging population; amyloid precursor protein processing; biological adaptation to stress; career; cofactor; density; drug discovery; experimental study; follow-up; genome-wide; insight; luminescence; member; neuroblastoma cell; neuronal growth; novel; oxidation; promoter; skills; small hairpin RNA; transcriptome; transcriptome sequencing

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.

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