Westermark Gunilla T, Nyström Ebba, Nyström Sofie, Nilsson K Peter R, Hammarström Per, Westermark Per
Department of Medical Cell Biology, Uppsala University, 75123, Uppsala, Sweden.
Department of Physics, Chemistry and Biology (IFM), Linköping University, 58183, Linköping, Sweden.
Sci Rep. 2025 Jan 29;15(1):3684. doi: 10.1038/s41598-025-87239-6.
The existence of transmissible amyloid fibril strains has long intrigued the scientific community. The strain theory originates from prion disorders, but here, we provide evidence of strains in systemic amyloidosis. Human AA amyloidosis manifests as two distinct clinical phenotypes called common AA and vascular AA. Glomerular amyloid deposition of the kidney defines the common form, while in the vascular type amyloid deposits are massive in the renal medulla and in arteries throughout the body, while glomeruli are spared. By electron microscopy the two types appeared morphologically different. The common type was composed of dispersed fibrils which tended to be clustered whereas the vascular type was composed of longer and more distinct less clustered fibrils. Staining with fluorescent amyloid binding ligands analyzed by hyperspectral microscopy showed differential staining patterns between the two groups supporting the notion of human AA amyloid strains. AA amyloid staining was significantly different from systemic AL amyloid. Both types of AA (common and vascular) and AL amyloid fibrils were isolated and used to seed mouse AA amyloid in groups of inflamed NMRI mice (n = 9-10 per group). All but two mice showed amyloid deposits in the spleen induced by the human seeds. Amyloid binding ligand analysis was applied on the splenic amyloid deposits and revealed no clear significant difference between mice seeded with AA fibrils from different donors being vascular or common, but the AA deposits of mice given AL fibrils showed significantly different amyloid fluorescent signals compared to all groups of mice receiving AA fibrils. The combined results support the hypothesis that AA amyloid fibril structures can vary depending on the seed and may manifest as amyloid strains.
可传播的淀粉样纤维毒株的存在长期以来一直引起科学界的兴趣。毒株理论起源于朊病毒疾病，但在此，我们提供了系统性淀粉样变性中存在毒株的证据。人类AA淀粉样变性表现为两种不同的临床表型，即普通型AA和血管型AA。肾脏的肾小球淀粉样沉积定义了普通型，而在血管型中，淀粉样沉积物在肾髓质和全身动脉中大量存在，而肾小球则未受影响。通过电子显微镜观察，这两种类型在形态上有所不同。普通型由分散的纤维组成，这些纤维往往聚集在一起，而血管型由更长、更明显且聚集较少的纤维组成。用荧光淀粉样结合配体染色并通过高光谱显微镜分析，结果显示两组之间存在差异染色模式，这支持了人类AA淀粉样毒株的概念。AA淀粉样染色与系统性AL淀粉样染色明显不同。将两种类型的AA（普通型和血管型）以及AL淀粉样纤维分离出来，并用于在一组发炎的NMRI小鼠（每组n = 9 - 10只）中引发小鼠AA淀粉样变性。除了两只小鼠外，所有小鼠的脾脏中都出现了由人类种子诱导的淀粉样沉积物。对脾脏中的淀粉样沉积物进行淀粉样结合配体分析，结果显示，用来自不同供体的血管型或普通型AA纤维接种的小鼠之间没有明显的显著差异，但与所有接受AA纤维的小鼠组相比，接受AL纤维的小鼠的AA沉积物显示出明显不同的淀粉样荧光信号。综合结果支持了这样一种假设，即AA淀粉样纤维结构可能因种子而异，并可能表现为淀粉样毒株。
