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化学进展 2020, Vol. 32 Issue (1): 14-22 DOI: 10.7536/PC191212 前一篇   后一篇

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截短与修饰的β-淀粉样蛋白与阿尔茨海默病

李高1,**(), 李艳梅2,3,4,**()   

  1. 1. 闽江学院海洋研究院 福州 350108
    2. 清华大学化学系 生命有机磷化学及化学生物学教育部重点实验室 北京 100084
    3. 北京脑重大疾病研究院 北京 100069
    4. 清华大学合成与系统生物学研究中心 北京 100084
  • 收稿日期:2019-12-16 出版日期:2020-01-15 发布日期:2020-01-08
  • 通讯作者: 李高, 李艳梅
  • 基金资助:
    国家重点研发计划(2018YFA0507600); 国家自然科学基金项目(81661148047); 闽江学院人才引进项目资助(MJY19025)
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Truncated and Modified Aβ Species in Alzheimer’s Disease

Gao Li1,**(), Yan-Mei Li2,3,4,**()   

  1. 1. Institute of Oceanography, Minjiang University, Fuzhou 350108, China
    2. Department of Chemistry, Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Tsinghua University, Beijing 100084, China
    3. Beijing Institute for Brain Disorders, Beijing 100069, China
    4. Center for Synthetic and Systems Biology, Tsinghua University, Beijing 100084, China
  • Received:2019-12-16 Online:2020-01-15 Published:2020-01-08
  • Contact: Gao Li, Yan-Mei Li
  • About author:
    ** E-mail: (Gao Li);
    (Yan-Mei Li)
  • Supported by:
    National Key Research and Development Program of China(2018YFA0507600); National Natural Science Foundation of China(81661148047); Talent Introduction Fund of Minjiang University(MJY19025)

β-淀粉样蛋白(Aβ)的聚集和沉积被认为是导致阿尔茨海默病的重要因素,早前的研究多集中在全长无修饰的Aβ1-40和Aβ1-42上。近些年研究发现,在AD患者大脑内存在着多种截短与修饰的Aβ蛋白,它们对AD的疾病进程有不可忽视的贡献。例如,焦谷氨酸Aβ、磷酸化Aβ被认为是AD患者出现症状的标志;截短的Aβ4-40/42在患者脑内的含量与Aβ1-40/42接近且具有类似的聚集性质和毒性;患者脑内氧化压力升高导致的酪氨酸硝基化、二聚化和甲硫氨酸氧化形式的Aβ也具有不同的性质。本文对这些截短与修饰的Aβ蛋白的产生、结构、毒性以及和AD的关联进行了综述。

关键词： β-淀粉样蛋白, 阿尔茨海默病, 截短, 磷酸化, 焦谷氨酸化

Aggregation of β-amyloid (Aβ) has been considered as an important factor leading to Alzheimer’s disease (AD). Previous studies have focused on the full-length unmodified Aβ1-40 and Aβ1-42. In recent years, it was found that a variety of truncated and modified Aβ species co-exist in AD patients’ brain. These Aβ species contributed to the progression of AD and should not be overlooked. For example, the emergence of pyroglutamated Aβ and phosphorylated Aβ is considered as symptoms of AD. And the most abundant Aβ species in AD patients’ brain should be Aβ4-40/42, which has similar aggregation properties and toxicity with Aβ1-40/42. Due to the elevated oxidative stress in AD patients’ brain, tyrosine nitration, dimerization and methionine oxidation were also identified in Aβ sequence, resulting in different properties. We review here the production, structure and toxicity of different Aβ species and summarize their possible roles in AD pathology.

Key words: β-amyloid;, Alzheimer’s disease;, truncation, phosphorylation, pyroglutamylation
()
图1 Aβ序列以及截短与修饰的位点[13]
Fig. 1 Sequence of Aβ and the sites for truncation or modification[13]
图2 针对焦谷氨酸Aβ的预防性疫苗[33]
Fig. 2 Prophylactic vaccine based on pyroglutamate-3 Aβ[33]. Copyright 2016 American Chemical Society
图3 不同截短与修饰的Aβ对原代神经元的毒性[35]
Fig. 3 Toxicity of different truncated and modified Aβ, tested on primary neurons[35]
图4 FRH序列与铜离子的可能结合模式
Fig. 4 Possible binding mode between FRH sequence and Cu2+
图5 26-位磷酸化阻断D23与K28之间的盐桥[45]
Fig. 5 Phosphorylation at 26-Ser could disturb the salt bridge between D23 and K28[45]. Copyright 2014 American Chemical Society
图6 合成的硝基化Aβ42的聚集与毒性[57]
Fig. 6 The aggregation and toxicity of synthetic Aβ42 [57]
图7 isoAsp23-Aβ20-34纤维晶体结构[78]
Fig. 7 Crystal structure of isoAsp23-Aβ20-34 fibril[78]
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