Asan Institute for Life Sciences, Asan Medical Center, Seoul 05505, Korea.
Department of Medical Science, Asan Medical Institute of Convergence Science and Technology, University of Ulsan College of Medicine, Seoul 05505, Korea.
Int J Mol Sci. 2020 Jan 25;21(3):802. doi: 10.3390/ijms21030802.
Zinc and apolipoprotein E (apoE) are reportedly involved in the pathology of Alzheimer's disease. To investigate the associative interaction among zinc, apoE, and amyloid-β (Aβ) and its role in amyloid pathogenesis, we performed various biochemical and immunoreactive analyses using brain tissues of Tg2576 mice and synthetic Aβ and apoE peptides. On amyloid plaques or in brain lysates of Tg2576 mice, apoE and Aβ immunoreactivities increased after zinc chelation and were restored by its subsequent replacement. Zinc depletion dissociated apoE/Aβ complexes or larger-molecular sizes of Aβ oligomers/aggregates into smaller-molecular sizes of apoE and/or Aβ monomers/complexes. In the presence of zinc, synthetic apoE and/or Aβ peptides aggregated into larger-molecular sizes of oligomers or complexes. Endogenous proteases or plasmin in brain lysates degraded apoE and/or Aβ complexes, and their proteolytic activity increased with zinc depletion. These biochemical findings suggest that zinc associates with apoE and Aβ to encourage the formation of apoE/Aβ complexes or large aggregates, raising the deposition of zinc-rich amyloid plaques. In turn, the presence of abundant zinc around and within apoE/Aβ complexes may block the access or activity of Aβ-degrading antibodies or proteases. These results support the plausibility of chelation strategy aiming at reducing amyloid pathology in Alzheimer's disease.
锌和载脂蛋白 E（apoE）据报道与阿尔茨海默病的病理学有关。为了研究锌、apoE 和淀粉样蛋白-β（Aβ）之间的关联相互作用及其在淀粉样蛋白发病机制中的作用，我们使用 Tg2576 小鼠的脑组织以及合成的 Aβ和 apoE 肽进行了各种生化和免疫反应分析。在 Tg2576 小鼠的淀粉样斑块或脑裂解物中，apoE 和 Aβ 免疫反应性在锌螯合后增加，并在随后的替换后得到恢复。锌耗竭将 apoE/Aβ 复合物或更大分子量的 Aβ寡聚物/聚集体解离成较小分子量的 apoE 和/或 Aβ单体/复合物。在锌存在的情况下，合成的 apoE 和/或 Aβ 肽聚集成更大分子量的寡聚物或复合物。脑裂解物中的内源性蛋白酶或纤溶酶降解 apoE 和/或 Aβ 复合物，并且随着锌耗竭，其酶解活性增加。这些生化发现表明，锌与 apoE 和 Aβ 结合，促进 apoE/Aβ 复合物或大聚集体的形成，增加富含锌的淀粉样斑块的沉积。反过来，apoE/Aβ 复合物周围和内部大量锌的存在可能会阻止 Aβ 降解抗体或蛋白酶的进入或活性。这些结果支持了旨在减少阿尔茨海默病中淀粉样蛋白病理学的螯合策略的合理性。
