SITE-SPECIFIC STUDIES PROVIDE STRUCTURAL INFORMATION ON AMYLOID BETA OLIGOMERS

特定位点研究提供了淀粉样β低聚物的结构信息

• 批准号: 8170990
• 负责人: Charles G. Glabe
• 金额: $ 1.8万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8170990
• 关键词: Alzheimer' s Disease; Amyloid beta-Protein; Antibodies; Computer Retrieval of Information on Scientific Projects Database; Cysteine; Disease Progression; Environment; Fluorescent Dyes; Funding; Grant; Hydrophobicity; Institution; Label; Measures; Pattern; Peptides; Property; Publishing; Research; Research Personnel; Resources; Role; Site; Source; Structure; United States National Institutes of Health; abeta accumulation; abeta oligomer; acrylodan; base; guanidine thiocyanate; interest; neurotoxicity; research study

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Aggregation of Abeta peptides is a major contributor to Alzheimer's disease. Oligomeric forms of these peptides are especially interesting due to their high neurotoxicity and potentially important role in disease progression. However, very little structural information is currently available on Abeta oligomers. We have previously established that Abeta oligomers can be divided into at least two structural classes (prefibrillar and fibrillar oligomers) based on their reactivity with conformational antibodies. Here we compared both site-specific and global conformational stability of Abeta 40 fibrils and both classes of oligomers. To measure the site-specific stability, we introduced cysteine residues throughout the sequence of Abeta 40, labeled the new cysteines with the fluorescent dye acrylodan, and investigated their environment within the aggregates in guanidine thiocyanate-induced denaturation experiments. We found that Abeta 40 fibrils show high stability towards denaturation and moderate hydrophobicity in the 15-35 region with the exception of residues 25-30. This pattern is consistent with previously published structures of Abeta 40 fibrils. Fibrillar oligomers show similar pattern consistent with our hypothesis that they represent fragments of protofibrils. However, prefibrillar oligomers show lower stability towards denaturation and more hydrophobic environment throughout the 15-35 region of the peptide. Distinct conformational properties of prefibrillar oligomers may explain their differential recognition by conformational antibodies and serve as a basis for their neurotoxicity.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 Abeta 肽的聚集是阿尔茨海默病的主要原因。这些肽的寡聚形式因其高神经毒性和在疾病进展中的潜在重要作用而特别令人感兴趣。然而，目前关于 Abeta 低聚物的结构信息非常少。我们之前已经确定，根据 Abeta 寡聚体与构象抗体的反应性，Abeta 寡聚体可以分为至少两个结构类别（前纤维寡聚体和纤维寡聚体）。在这里，我们比较了 Ab​​eta 40 原纤维和两类寡聚物的位点特异性和整体构象稳定性。为了测量位点特异性稳定性，我们在 Abeta 40 的整个序列中引入了半胱氨酸残基，用荧光染料 acrylodan 标记新的半胱氨酸，并在硫氰酸胍诱导的变性实验中研究了它们在聚集体中的环境。我们发现 Abeta 40 原纤维在 15-35 区域（残基 25-30 除外）表现出对变性的高度稳定性和中等疏水性。该模式与先前发表的 Abeta 40 原纤维的结构一致。纤维状寡聚体表现出类似的模式，与我们的假设一致，即它们代表原纤维的片段。然而，前原纤维寡聚物对变性表现出较低的稳定性，并且在整个肽的 15-35 区域显示出更多的疏水性环境。前原纤维寡聚物的独特构象特性可以解释构象抗体对它们的差异识别，并作为其神经毒性的基础。