Signatures of modified Abeta peptides in brains of Alzheimer’s disease subjects revealed by novel monoclonal antibodies

新型单克隆抗体揭示了阿尔茨海默病受试者大脑中修饰的 Abeta 肽的特征

• 批准号: 426452260
• 负责人: Professor Dr. Steffen Roßner
• 金额: --
• 依托单位: Hochschule Anhalt
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2023-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/426452260?language=en
• 关键词: Signatures; modified; Abeta; peptides; brains

In this proposal we would like to test the hypothesis that defined Abeta peptide variants contribute to the pathogenesis and progression of Alzheimer’s disease (AD) in a specific manner. Deposits of Abeta peptides in amyloid plaques are a histopathological hallmark of AD. However, it is generally accepted that not amyloid plaques, but their oligomeric and fibrillary precursors compromise neuronal function and are neurotoxic. Abeta peptides represent a heterogeneous group of peptides with differing biophysical and cell biological characteristics that are diversified by N-terminal truncation and other specific post-translational modifications. However, the contributions of defined Abeta peptide variants to the initiation and progression of AD are not fully established. Therefore, we would like to employ already existing and novel monoclonal antibodies generated by us for the comparative analyses of phosphorylated, nitrated, pyroglutamate- and isoaspartate-modified Abeta peptides in brain parenchyma and vessels by immunohistochemical and biochemical methods. We will analyze post mortem human brain tissue from pre-symptomatic and symptomatic AD cases in comparison to brain tissue from control subjects and subjects who suffered from vascular dementia and from dementia with Lewy bodies. Additionally, we will reveal aggregation characteristics and neurotoxic profiles of modified Abeta peptides in primary neuronal cell cultures. In summary, the results should reveal whether these modified forms of Abeta might represent potent drivers of disease progression due to their spatial and temporal expression patterns in brain and neurotoxicity.

在这个提议中，我们想测试的假设，即定义的Abeta肽变体有助于阿尔茨海默病（AD）的发病机制和进展，以特定的方式。淀粉样斑块中的A β肽沉积是AD的组织病理学标志。然而，人们普遍认为，不是淀粉样蛋白斑块，而是其寡聚体和非淀粉样前体损害神经元功能并具有神经毒性。Abeta肽代表具有不同生物物理和细胞生物学特征的肽的异质组，其通过N-末端截短和其他特异性翻译后修饰而多样化。然而，定义的Abeta肽变体对AD的启动和进展的贡献尚未完全确定。因此，我们想采用现有的和新的单克隆抗体，我们产生的比较分析磷酸化，硝化，焦谷氨酸和异谷氨酸修饰的Abeta肽在脑实质和血管的免疫组织化学和生物化学方法。我们将分析尸检人脑组织从症状前和症状性AD病例相比，脑组织从对照组和受试者谁患有血管性痴呆和路易体痴呆。此外，我们还将揭示原代神经元细胞培养物中修饰的Abeta肽的聚集特性和神经毒性特征。总之，结果应该揭示这些修饰形式的Abeta是否可能代表疾病进展的有力驱动因素，因为它们在大脑和神经毒性中的空间和时间表达模式。