Intermediate antiparallel fibrils in Aβ40 Dutch mutant aggregation: nanoscale insights from AFM-IR.
Intermediate antiparallel fibrils in Aβ40 Dutch mutant aggregation: nanoscale insights from AFM-IR.
复制标题
Aβ40 荷兰突变体聚集中的中间反平行原纤维：来自 AFM-IR 的纳米级见解。
DOI：
10.1101/2023.03.21.533667
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Ghosh,Ayanjeet
中科院分区：
文献类型：
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作者：
Banerjee,Siddhartha;Naik,Tanmayee;Ghosh,Ayanjeet
脑淀粉样血管病（CAA），涉及血管中的淀粉样蛋白沉积，导致致命的脑出血和复发性中风，存在于大多数阿尔茨海默病病例中。淀粉样β肽的家族性突变与CAA的高风险相关，并且主要由残基22和23处的突变组成。虽然野生型Aβ肽的结构已被非常详细地研究，但对CAA中涉及的突变体的结构及其进化知之甚少。对于残基22处的突变尤其如此，对于这些突变，不存在详细的分子结构，如通常由核磁共振（NMR）光谱或电子显微镜测定的。在这份报告中，我们使用了纳米级红外（IR）光谱与原子力显微镜（AFM-IR）增强，以研究在单一聚集体水平的Aβ荷兰突变体（E22 Q）的结构演变。我们表明，在寡聚阶段，结构系综是明显的双峰，与两个亚型不同的人口的平行β-折叠。另一方面，原纤维在结构上是均匀的，早期原纤维具有明显的反平行特征，其在成熟时形成平行的β-折叠。此外，反平行结构被发现是一个持久的功能，在不同阶段的聚合。
Cerebral Amyloid Angiopathy (CAA), which involves amyloid deposition in blood vessels leading to fatal cerebral hemorrhage and recurring strokes, is present in the majority Alzheimer’s disease cases. Familial mutations in the amyloid β peptide is correlated to higher risks of CAA, and are mostly comprised of mutations at residues 22 and 23. While the structure of the wild type Aβ peptide has been investigated in great detail, less is known about the structure of mutants involved in CAA and evolutions thereof. This is particularly true for mutations at residue 22, for which detailed molecular structures, as typically determined from Nuclear Magnetic Resonance (NMR) spectroscopy or electron microscopy, do not exist. In this report, we have used nanoscale infrared (IR) spectroscopy augmented with Atomic Force Microscopy (AFM-IR) to investigate structural evolution of the Aβ Dutch mutant (E22Q) at the single aggregate level. We show that that in the oligomeric stage, the structural ensemble is distinctly bimodal, with the two subtypes differing with respect to population of parallel β-sheets. Fibrils on the other hand are structurally homogeneous, with early-stage fibrils distinctly anti parallel in character, which develop parallel β-sheets upon maturation. Furthermore, the antiparallel structure is found to be a persistent feature across different stages of aggregation.