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

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.