Design, characterization, and use of a novel amyloid ß-protein control for assembly, neurotoxicity, and gene expression studies

A key pathogenic agent in Alzheimer’s disease (AD) is the amyloid ß-protein (Aß), which self-assembles into a variety of neurotoxic structures. Establishing structure-activity relationships for these assemblies is critical for proper therapeutic target identification and design. We examined the effects of Aß monomers, dimers, higher-order oligomers, and fibrils on gene expression in primary rat hippocampal neurons. As opposed to “reverse” Aß or non-Aß peptides typically used as controls in such studies, we designed novel scrambled Aß peptides predicted to behave distinctly from native Aß. Significant changes in gene expression were observed for all peptide assemblies, but fibrils induced the largest changes. Significant changes in gene expression were observed for all peptide assemblies, but fibrils induced the largest changes. Weighted gene co-expression network analysis (WGCNA) revealed two predominant gene modules related to Aß treatment. Many genes within these modules were associated with inflammatory signaling pathways阿尔茨海默病（Alzheimer’s disease, AD）的关键致病因子为β淀粉样蛋白（amyloid ß-protein, Aß），该蛋白可自组装形成多种神经毒性结构。明确此类聚集体的构效关系，对于精准开展治疗靶点识别与药物设计至关重要。本研究以原代大鼠海马神经元为模型，探究了Aß单体、二聚体、高阶寡聚体及原纤维对基因表达的影响。相较于此类研究中常用作对照的'反向'Aß肽或非Aß肽，我们设计了全新的乱序Aß肽，经预测其行为与天然Aß存在显著差异。所有肽聚集体均引发了显著的基因表达变化，其中原纤维诱导的表达改变幅度最大。加权基因共表达网络分析（weighted gene co-expression network analysis, WGCNA）揭示了两个与Aß处理相关的核心基因模块，模块内大量基因均与炎症信号通路密切相关。