Department of Chemistry and Biochemistry, The University of Alabama, 1007E Shelby Hall, Tuscaloosa, Alabama 35487, United States.
J Phys Chem B. 2022 Aug 11;126(31):5832-5841. doi: 10.1021/acs.jpcb.2c04797. Epub 2022 Aug 1.
Amyloid plaques are one of the central manifestations of Alzheimer's disease pathology. Aggregation of the amyloid beta (Aβ) protein from amorphous oligomeric species to mature fibrils has been extensively studied. However, structural heterogeneities in prefibrillar species, and how that affects the structure of later-stage aggregates are not yet well understood. The integration of infrared spectroscopy with atomic force microscopy (AFM-IR) allows for identifying the signatures of individual nanoscale aggregates by spatially resolving spectra. We use AFM-IR to demonstrate that amyloid oligomers exhibit significant structural variations as evidenced in their infrared spectra. This heterogeneity is transmitted to and retained in protofibrils and fibrils. We show that amyloid fibrils do not always conform to their putative ordered structure and structurally different domains exist in the same fibril. We further demonstrate that these structural heterogeneities manifest themselves as a lack of β sheet structure in amyloid plaques in Alzheimer's tissue using infrared imaging.
淀粉样斑块是阿尔茨海默病病理学的主要表现形式之一。β淀粉样蛋白（Aβ）从无定形寡聚体到成熟原纤维的聚集已被广泛研究。然而，原纤维前体物种的结构异质性，以及这如何影响后期聚集物的结构尚不清楚。红外光谱与原子力显微镜（AFM-IR）的结合允许通过空间分辨光谱来识别各个纳米级聚集体的特征。我们使用 AFM-IR 证明了淀粉样寡聚体表现出明显的结构变化，这在其红外光谱中得到了证明。这种异质性传递到原纤维和纤维中，并得以保留。我们表明，淀粉样纤维并不总是符合其假定的有序结构，并且在同一纤维中存在结构不同的区域。我们进一步证明，这些结构异质性表现为阿尔茨海默病组织中的淀粉样斑块中缺乏β片层结构，这可以通过红外成像来实现。
