Structure and propagation of beta-amyloid aggregates

β-淀粉样蛋白聚集体的结构和增殖

• 批准号: 214743469
• 负责人: Professor Dr. Marcus Fändrich
• 金额: --
• 依托单位: Institut für Proteinbiochemie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2012
• 资助国家: 德国
• 起止时间: 2011-12-31 至 2014-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/214743469?language=en
• 关键词: Structure; propagation; beta; amyloid; aggregates

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.

淀粉样蛋白(β-β)多肽以淀粉样纤维的形式沉积，是神经退行性疾病的标志，如脑淀粉样血管病和阿尔茨海默病。这些事件背后是一种分子自组装反应，这种反应可以通过预先形成的淀粉样纤维在体外播种，在体内则可以通过向阿尔茨海默病小鼠模型脑内注射含有Aβ的脑提取物来进行。虽然脑提取物的体内播种活性被证明严重依赖于Aβ肽，但淀粉样蛋白传播的进一步决定因素仍然是个谜。体外制备的Aβ多肽不能有效地诱导小鼠Aβ淀粉样变性，提示Aβ多肽的特定构象或目前未知的分子辅因子参与了这一过程。为了解决这些问题和解决不同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。这些预期的结果旨在对淀粉样蛋白错误折叠疾病的构象基础有新的见解，并将与理解从淀粉样聚集体扩散到分子菌株发展的相关生物学现象相关。

项目成果

Enhanced Fibril Fragmentation of N-Terminally Truncated and Pyroglutamyl-Modified Aβ Peptides.

N 末端截短和焦谷氨酰修饰 Aβ 肽的增强原纤维断裂

• DOI: 10.1002/anie.201511099
• 发表时间: 2016
• 期刊: Angewandte Chemie
• 作者: Wulff M;Baumann M;Thümmler A;Yadav JK;Heinrich L;Knüpfer U;Schlenzig D;Schierhorn A;Rahfeld JU;Horn U;Balbach J;Demuth HU;Fändrich M
• 通讯作者: Fändrich M

Molecular architecture of Aβ fibrils grown in cerebrospinal fluid solution and in a cell culture model of Aβ plaque formation

在脑脊液溶液和 Aβ 斑块形成​​的细胞培养模型中生长的 Aβ 原纤维的分子结构

• DOI: 10.3109/13506129.2016.1146989
• 发表时间: 2016
• 期刊: Amyloid
• 影响因子: 5.5
• 作者: Garvey M;Baumann M;Wulff M;Kumar ST;Markx D;Morgado I;Knüpfer U;Horn U;Mawrin C;Fändrich M;Balbach J
• 通讯作者: Balbach J