Álvarez-Marimon Elena, Castillo-Michel Hiram, Reyes-Herrera Juan, Seira Jofre, Aso Ester, Carmona Margarita, Ferrer Isidre, Cladera Josep, Benseny-Cases Núria
Unitat de Biofísica, Departament de Bioquímica i de Biologia Molecular, Facultat de Medicina, Universitat Autonoma de Barcelona, 08193 Cerdanyola del Vallès, Catalonia, Spain.
ID21, European Synchrotron Radiation Facility (ESRF), 71 Avenue des Martyrs, 38043 Grenoble, France.
ACS Chem Neurosci. 2021 Jun 2;12(11):1961-1971. doi: 10.1021/acschemneuro.1c00048. Epub 2021 May 14.
Amyloid plaques are one of the principal hallmarks of Alzheimer's disease and are mainly composed of Aβ amyloid peptides together with other components such as lipids, cations, or glycosaminoglycans. The structure of amyloid peptide's aggregates is related to the peptide toxicity and highly depends on the aggregation conditions and the presence of cofactors. While fibrillary aggregates are nowadays considered nontoxic, oligomeric/granular (nonfibrillary) aggregates have been found to be toxic. In this work we have characterized two different types of amyloid deposits analyzing sections of the cortex of patients in advanced stages of Alzheimer disease. By combining SR-μFTIR for the study of the secondary structure of the peptide and ThS fluorescence as an indicator of fibrillary structures, we found two types of plaques: ThS positive plaques with a clear infrared band at 1630 cm that would correspond to fibrillary plaques and ThS negative plaques showing a mixture of nonfibrillar β-sheet and unordered aggregated structures that would correspond to the nonfibrillary plaques (plaques with increased unordered structure). The analysis of the FTIR spectra has allowed correlation of lipid oxidation with the presence of nonfibrillary plaques. The metal composition of the two types of plaques has been analyzed using SR-nano-XRF and XANES. The results have shown higher accumulation of iron (mainly Fe) in fibrillary plaques than in nonfibrillary ones. However, in nonfibrillary plaques Fe has been found to predominate over Fe. The identification of different types of aggregated forms and the different composition of metals found in the different types of plaques could be of paramount importance for the understanding of the development of Alzheimer disease.
淀粉样斑块是阿尔茨海默病的主要标志之一，主要由Aβ淀粉样肽与其他成分如脂质、阳离子或糖胺聚糖组成。淀粉样肽聚集体的结构与肽的毒性相关，并且高度依赖于聚集条件和辅因子的存在。虽然如今认为纤维状聚集体无毒，但已发现寡聚体/颗粒状（非纤维状）聚集体具有毒性。在这项工作中，我们通过分析阿尔茨海默病晚期患者皮质切片，对两种不同类型的淀粉样沉积物进行了表征。通过结合用于研究肽二级结构的同步辐射傅里叶变换红外光谱（SR-μFTIR）和作为纤维状结构指标的硫黄素T（ThS）荧光，我们发现了两种类型的斑块：在1630 cm处有清晰红外波段的ThS阳性斑块，这将对应于纤维状斑块；以及ThS阴性斑块，显示出非纤维状β-折叠和无序聚集结构的混合物，这将对应于非纤维状斑块（无序结构增加的斑块）。傅里叶变换红外光谱（FTIR）的分析使得脂质氧化与非纤维状斑块的存在相关联。使用同步辐射纳米X射线荧光光谱（SR-nano-XRF）和X射线吸收近边结构（XANES）分析了两种类型斑块的金属组成。结果表明，纤维状斑块中铁（主要是Fe）的积累高于非纤维状斑块。然而，在非纤维状斑块中发现Fe比Fe占主导地位。识别不同类型的聚集形式以及在不同类型斑块中发现的不同金属组成对于理解阿尔茨海默病的发展可能至关重要。
