Hubei Key Laboratory of Bioinorganic Chemistry and Materia Medica, School of Chemistry and Chemical Engineering, Huazhong University of Science and Technology, Wuhan, Hubei 430074, People's Republic of China.
Chem Res Toxicol. 2013 Feb 18;26(2):262-9. doi: 10.1021/tx300441e. Epub 2013 Jan 15.
Amyloid β peptide (Aβ) aggregation is a pathological hallmark of Alzheimer's disease (AD). Modulation of the self-assembly processes, therefore, is thought to be an attractive strategy for the prevention and treatment of AD. Interestingly, heme has been found to inhibit Aβ aggregation and even dismantle Aβ aggregates. However, the mechanism remains unresolved. Recent research has shown that heme binds preferentially to the His(13) residue of Aβ with the iron center, while the hydrophobic domain of Aβ is also able to bind to heme. Herein, absorption spectrometric, Thioflavin T fluorescence, and circular dichroism spectroscopic and transmission electron microscopic measurements revealed that the iron center is not required for the inhibition of Aβ aggregation but do influence the binding affinity of heme toward Aβ and the dismantlement rate and degree of the Aβ aggregates. By studying the interaction of different truncated or mutated Aβ peptides with heme or protoporphyrin, we further found that the porphyrin ring of heme is implicated to interact preferentially with the Phe(19) residue, facilitating the binding of heme to Aβ and disturbing the interstrand aromatic interaction between the Phe residues, which is crucial for Aβ fibrillation. These findings open new avenues in the understanding of the interaction between the heme and Aβ and the pathways for modulation of Aβ aggregation and disaggregation, which would be helpful in designing therapeutic strategies against AD.
淀粉样 β 肽（Aβ）聚集是阿尔茨海默病（AD）的病理标志。因此，调节自组装过程被认为是预防和治疗 AD 的一种有吸引力的策略。有趣的是，已经发现血红素可以抑制 Aβ聚集，甚至可以拆开 Aβ 聚集体。然而，其机制仍未解决。最近的研究表明，血红素优先与 Aβ 的 His(13)残基结合，其中铁中心，而 Aβ 的疏水区也能够与血红素结合。在此，吸收光谱、硫黄素 T 荧光、圆二色光谱和透射电子显微镜测量表明，铁中心对于抑制 Aβ 聚集不是必需的，但会影响血红素与 Aβ 的结合亲和力以及 Aβ 聚集体的拆开速率和程度。通过研究不同截断或突变的 Aβ 肽与血红素或原卟啉的相互作用，我们进一步发现血红素的卟啉环优先与 Phe(19)残基相互作用，促进血红素与 Aβ 的结合并扰乱 Phe 残基之间的链间芳香相互作用，这对于 Aβ 原纤维形成至关重要。这些发现为理解血红素与 Aβ 之间的相互作用以及调节 Aβ 聚集和解聚的途径开辟了新的途径，这有助于设计针对 AD 的治疗策略。
