Banerjee Siddhartha, Naik Tanmayee, Ghosh Ayanjeet
Department of Chemistry and Biochemistry, The University of Alabama, 1007E Shelby Hall, Tuscaloosa, Alabama 35487, United States.
bioRxiv. 2023 Mar 23:2023.03.21.533667. doi: 10.1101/2023.03.21.533667.
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.
脑淀粉样血管病（CAA），其涉及淀粉样蛋白在血管中的沉积，可导致致命性脑出血和复发性中风，在大多数阿尔茨海默病病例中都存在。淀粉样β肽的家族性突变与CAA的较高风险相关，且大多由22位和23位残基处的突变组成。虽然野生型Aβ肽的结构已得到详细研究，但对于与CAA相关的突变体的结构及其演变了解较少。对于22位残基处的突变尤其如此，目前不存在通常由核磁共振（NMR）光谱或电子显微镜确定的详细分子结构。在本报告中，我们使用了结合原子力显微镜的纳米级红外（IR）光谱（AFM - IR）来研究Aβ荷兰突变体（E22Q）在单个聚集体水平上的结构演变。我们表明，在寡聚阶段，结构整体明显呈双峰分布，两种亚型在平行β - 折叠的数量上有所不同。另一方面，纤维在结构上是均匀的，早期纤维明显具有反平行特征，成熟后会形成平行β - 折叠。此外，反平行结构在聚集的不同阶段都是一个持久的特征。
