Site-specific glycation of Aβ1–42 affects fibril formation and is neurotoxic
Site-specific glycation of Aβ1–42 affects fibril formation and is neurotoxic
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Aβ1-42 的位点特异性糖化会影响原纤维形成并具有神经毒性
DOI：
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发表时间：
2019
影响因子：
4.8
通讯作者：
N. Birch
中科院分区：
文献类型：
--
作者：
Jin Ng;H. Kaur;T. Collier;Kevin Chang;A. Brooks;Jane R. Allison;M. Brimble;A. Hickey;N. Birch
β1-42参与阿尔茨海默病(AD)的发病机制，并易于糖基化，这是一个不可逆转的过程，蛋白质积累晚期糖化最终产物(AGEs)。N-(羧乙基)赖氨酸是AD患者常见的年龄，发生在Aϵ1-42的Lys-16或Lys-28。甲乙二醛通常用于Aβ1-42的非特异性糖基化，这会导致AGE修饰的多肽的复杂混合物，并使解释特定氨基酸残基的致病年龄变得困难。我们通过化学合成Aβ1-42在Lys-16(Aβ-CEL16)、Lys-28(Aβ-CEL28)以及Lys-16和-28(Aβ-CEL16&28)上定义的CEL修饰来解决这个问题。我们证明了Aβ1-42的Lys-16和Lys-28处的双细胞阳离子对形成淀粉样纤维的能力有最深刻的影响。在计算机预测中表明，Aβ-CEL16&28的自由能变化显著减少，这有助于纤维失稳，并增加了聚集率。Aβ1-42的Lys-28位的单细胞阳离子对纤维形成的影响最小，而Aβ1-42的Lys-16的单细胞阳离子延迟了纤维的形成。我们还在维甲酸分化的SH-SY5Y人神经母细胞瘤细胞系(RA分化的SH-SY5Y)上测试了这些肽的神经元毒性和线粒体功能。只有Aβ-CEL16和Aβ-CEL28具有神经毒性，可能通过非线粒体途径，而Aβ-CEL16&28没有神经毒性。有趣的是，Aβ-CEL16&28使线粒体膜电位去极化，而Aβ-CEL16增加了复合体II的线粒体呼吸。这些结果可能分别表明有丝分裂或另一种代谢途径。因此，我们的结果为针对神经细胞毒性糖化Aβ1-42的潜在治疗方法提供了洞察力。
Aβ1–42 is involved in Alzheimer's disease (AD) pathogenesis and is prone to glycation, an irreversible process where proteins accumulate advanced glycated end products (AGEs). Nϵ-(Carboxyethyl)lysine (CEL) is a common AGE associated with AD patients and occurs at either Lys-16 or Lys-28 of Aβ1–42. Methyglyoxal is commonly used for the unspecific glycation of Aβ1–42, which results in a complex mixture of AGE-modified peptides and makes interpretation of a causative AGE at a specific amino acid residue difficult. We address this issue by chemically synthesizing defined CEL modifications on Aβ1–42 at Lys-16 (Aβ-CEL16), Lys-28 (Aβ-CEL28), and Lys-16 and -28 (Aβ-CEL16&28). We demonstrated that double-CEL glycations at Lys-16 and Lys-28 of Aβ1–42 had the most profound impact on the ability to form amyloid fibrils. In silico predictions indicated that Aβ-CEL16&28 had a substantial decrease in free energy change, which contributes to fibril destabilization, and a increased aggregation rate. Single-CEL glycations at Lys-28 of Aβ1–42 had the least impact on fibril formation, whereas CEL glycations at Lys-16 of Aβ1–42 delayed fibril formation. We also tested these peptides for neuronal toxicity and mitochondrial function on a retinoic acid-differentiated SH-SY5Y human neuroblastoma cell line (RA-differentiated SH-SY5Y). Only Aβ-CEL16 and Aβ-CEL28 were neurotoxic, possibly through a nonmitochondrial pathway, whereas Aβ-CEL16&28 showed no neurotoxicity. Interestingly, Aβ-CEL16&28 had depolarized the mitochondrial membrane potential, whereas Aβ-CEL16 had increased mitochondrial respiration at complex II. These results may indicate mitophagy or an alternate route of metabolism, respectively. Therefore, our results provides insight into potential therapeutic approaches against neurotoxic CEL-glycated Aβ1–42.
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影响因子：
4.1
作者：
Ahmed, MU;Frye, EB;Baynes, JW
通讯作者：
Baynes, JW
影响因子：
14.8
作者：
Bieschke, Jan;Herbst, Martin;Wanker, Erich E.
通讯作者：
Wanker, Erich E.
影响因子：
1.6
作者：
T. Degenhardt;S. Thorpe;J. Baynes
通讯作者：
T. Degenhardt;S. Thorpe;J. Baynes
DOI：
10.1007/978-1-62703-640-5_2
发表时间：
2013
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
--
作者：
Kovalevich, Jane;Langford, Dianne
通讯作者：
Langford, Dianne
DOI：
10.1042/bj3500381
发表时间：
2000-09
期刊：
The Biochemical journal
影响因子：
--
作者：
N. Verzijl;J. DeGroot;Esther Oldehinkel;R. Bank;S. Thorpe;J. Baynes;M. Bayliss;J. Bijlsma;
通讯作者：
N. Verzijl;J. DeGroot;Esther Oldehinkel;R. Bank;S. Thorpe;J. Baynes;M. Bayliss;J. Bijlsma;