Iminodiacetic Acid-Modified Human Serum Albumin: A Multifunctional Agent against Metal-Associated Amyloid β-Protein Aggregation and Cytotoxicity,ACS Chemical Neuroscience

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Iminodiacetic Acid-Modified Human Serum Albumin: A Multifunctional Agent against Metal-Associated Amyloid β-Protein Aggregation and Cytotoxicity
ACS Chemical Neuroscience ( IF 4.1 ) Pub Date : 2017-08-14 00:00:00 , DOI: 10.1021/acschemneuro.7b00128
Baolong Xie ₁ , Huan Zhang ₁ , Xi Li ₁ , Xiaoyan Dong ₁ , Yan Sun ₁

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Metal-induced amyloid β-protein (Aβ) aggregation plays a key role in the pathogenesis of Alzheimer’s disease. Although several agents have been recognized to block metal-associated Aβ aggregation, their therapeutic potential is marred due to the high-concentration metal ions in the amyloid plaques. To overcome this problem, we have herein developed iminodiacetic acid-modified human serum albumin (I-HSA) to fight against the aggregation. The multifunctional nature of I-HSA was extensively characterized in inhibiting the Aβ₄₂ aggregation associated with Zn²⁺ and Cu²⁺. The results revealed the following: (1) I-HSA significantly inhibited Aβ₄₂ aggregation and alleviated its cytotoxicity. (2) I-HSA possessed a metal-chelate capacity as high as 31.2 mol/mol, and 25 μM I-HSA could effectively inhibit the influence of 250 μM Zn²⁺ on Aβ₄₂ aggregation. (3) Equimolar I-HSA remarkably attenuated the reactive oxygen species damage caused by the Aβ₄₂ and Cu²⁺–Aβ₄₂ species. (4) I-HSA could remodel metal–Aβ₄₂ fibrils into unstructured aggregates with less neurotoxicity. The cytotoxicity of mature Cu²⁺–Aβ₄₂ aggregates was mitigated from 64.8% to 25.4% under the functioning of I-HSA. In conclusion, I-HSA showed prominent advantages for the high metal-chelate capacity. To our knowledge, I-HSA is the first multifunctional macromolecule for inhibiting high-concentration metal-induced Aβ₄₂ aggregation and remodeling mature metal-induced Aβ₄₂ species.

中文翻译：

亚氨基二乙酸修饰的人血清白蛋白：对抗金属相关淀粉样β蛋白聚集和细胞毒性的多功能剂。

金属诱导的淀粉样β蛋白（Aβ）聚集在阿尔茨海默氏病的发病机理中起关键作用。尽管已经认识到有几种药物可以阻止金属相关的Aβ聚集，但是由于淀粉样蛋白斑块中的高浓度金属离子，其治疗潜力受到了损害。为了克服这个问题，我们在这里开发了亚氨基二乙酸修饰的人血清白蛋白（I-HSA）以对抗聚集。I-HSA的多功能性质在抑制与Zn ²⁺和Cu ²⁺相关的_Aβ42聚集方面具有广泛的特征。结果表明：（1）I-HSA显着抑制_Aβ42聚集并减轻其细胞毒性。（2）I-HSA具有高达31.2 mol / mol的金属螯合物容量，而25μMI-HSA可以有效抑制250μMZn ²⁺对_Aβ42聚集的影响。（3）将等摩尔I-HSA显着地衰减的活性氧伤害的Aβ引起₄₂和Cu ²⁺ -Aβ ₄₂种。（4）I-HSA可以重塑金属Aβ _42个原纤维成非结构化聚集体具有较少的神经毒性。成熟的Cu ²⁺ –Aβ ₄₂的细胞毒性在I-HSA的作用下，骨料从64.8％减少到25.4％。总之，I-HSA在高金属螯合物容量方面显示出显着优势。据我们所知，I-HSA是第一个抑制高浓度金属诱导的_Aβ42聚集并重塑成熟金属诱导的_Aβ42物种的多功能大分子。

更新日期：2017-08-14

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