Lu Naihao, Li Jiayu, Tian Rong, Peng Yi-Yuan
Key Laboratory of Functional Small Organic Molecule, Ministry of Education and College of Life Science, ‡Key Laboratory of Green Chemistry, Jiangxi Province and College of Chemistry and Chemical Engineering, Jiangxi Normal University , 99 Ziyang Road, Nanchang, Jiangxi 330022, China.
Chem Res Toxicol. 2015 Mar 16;28(3):365-72. doi: 10.1021/tx5003035. Epub 2014 Sep 24.
Amyloid β-peptide (Aβ) aggregation in the brain, known as amyloid plaques, is a pathological feature of Alzheimer's disease (AD). Recent studies show that heme binds to the His residue of Aβ with the iron center and subsequently forms an Aβ-heme complex, which can inhibit Aβ aggregation. Although Tyr-10 was not the residue binding heme, the key roles for Tyr-10 in Aβ-heme complexes and its potential biological relevance to AD etiology under oxidative stress were not sufficiently evaluated. Here, we used wild-type and Tyr-10-mutated human Aβ peptides and studied the impact of the mutation on Aβ-heme peroxidase activity, heme-bound Aβ aggregation, and oxidation and nitration under oxidative and nitrative stresses. Our results indicate that the mutation of Tyr-10 in Aβ16 and Aβ40 decreased the peroxidase activity of Aβ-heme complexes and that the mutation of Tyr-10 could inhibit Aβ40 self-assembly aggregation. Under oxidative (H2O2) and nitrative (H2O2/NaNO2) stress conditions, the Aβ40-heme complexes caused oxidation and nitration of the Aβ Tyr-10 residue through promoting peroxidase-like reactions, which were different from the classic inhibitive effect of heme on Aβ aggregation. To our knowledge, this is the first time that the formation of a heme-to-protein cross-linked Aβ40-heme complex under oxidative stress has been reported; in addition, the mutation of Tyr-10 could inhibit the cross-link formation. Therefore, Tyr-10 is pivotal in Aβ-heme complexes and plays key roles in Aβ aggregation under oxidative and nitrative stresses, demonstrating a novel significance of Tyr-10 as well as Aβ-heme complexes in the pathology of AD.
大脑中淀粉样β肽（Aβ）聚集形成淀粉样斑块，是阿尔茨海默病（AD）的一个病理特征。最近的研究表明，血红素通过铁中心与Aβ的组氨酸残基结合，随后形成Aβ-血红素复合物，该复合物可抑制Aβ聚集。尽管酪氨酸-10并非与血红素结合的残基，但酪氨酸-10在Aβ-血红素复合物中的关键作用及其在氧化应激下与AD病因学潜在的生物学相关性尚未得到充分评估。在此，我们使用野生型和酪氨酸-10突变的人Aβ肽，研究了该突变对Aβ-血红素过氧化物酶活性、血红素结合的Aβ聚集以及氧化应激和硝化应激下的氧化和硝化作用的影响。我们的结果表明，Aβ16和Aβ40中酪氨酸-10的突变降低了Aβ-血红素复合物的过氧化物酶活性，并且酪氨酸-10的突变可以抑制Aβ40的自组装聚集。在氧化（H2O2）和硝化（H2O2/NaNO2）应激条件下，Aβ40-血红素复合物通过促进类过氧化物酶反应导致Aβ酪氨酸-10残基的氧化和硝化，这与血红素对Aβ聚集的经典抑制作用不同。据我们所知，这是首次报道在氧化应激下形成血红素与蛋白质交联的Aβ40-血红素复合物；此外，酪氨酸-10的突变可以抑制交联的形成。因此，酪氨酸-10在Aβ-血红素复合物中至关重要，并在氧化和硝化应激下的Aβ聚集中起关键作用，这证明了酪氨酸-10以及Aβ-血红素复合物在AD病理学中的新意义。
