Structure and propagation of beta-amyloid aggregates

β-淀粉样蛋白（Aβ）肽作为淀粉样蛋白原纤维的沉积是神经退行性疾病（如脑淀粉样血管病和阿尔茨海默病）的标志。这些事件的基础是分子自组装反应，该反应可以通过预先形成的淀粉样蛋白原纤维在体外接种，并通过将含Aβ的脑提取物脑内注射到阿尔茨海默病小鼠模型中在体内接种。虽然脑提取物的体内接种活性显示严重依赖于Aβ肽，但淀粉样蛋白增殖的其他决定因素仍然是谜。体外制备的Aβ肽不能有效诱导小鼠Aβ淀粉样变性，这表明Aβ肽的特定构象或目前未知的分子辅因子参与其中。为了解决这些问题并解析不同Aβ聚集体的分子构象，我们将采用一系列生物物理和生物技术，从结构生物学和分析化学到动物研究。预期的结果旨在为淀粉样蛋白错误折叠疾病的构象基础的新见解，他们将是相关的了解相关的生物学现象，从淀粉样蛋白聚集体的传播到分子菌株的发展。

The deposition of β-amyloid (Aβ) peptide as amyloid fibrils is a hallmark of neurodegenerative conditions, such as cerebral amyloid angiopathy and Alzheimer’s disease. Underlying these events is a molecular self-assembly reaction that can be seeded in vitro by preformed amyloid fibrils and in vivo by intracerebral injection of Aβ-containing brain extracts into Alzheimer mouse models. While the in vivo seeding activity of brain extracts was shown to critically depend on Aβ peptide, the further determinants of amyloid propagation have remained enigmatic. In vitro preparations of Aβ peptide did not efficiently induce Aβ amyloidosis in mice, suggesting the involvement of a specific conformation of Aβ peptide or a currently unknown molecular cofactor. To address these issues and to resolve the molecular conformations of different Aβ aggregates, we will employ a battery of biophysical and biological techniques, ranging from structural biology and analytical chemistry to animal studies. The expected results aim for new insights into the conformational basis of amyloidotic protein misfolding diseases, and they will be relevant for understanding related biological phenomena from the spreading of amyloid aggregates to the development of molecular strains.