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Apolipoprotein E impairs amyloid-β fibril elongation and maturation.
The FEBS Journal ( IF 5.5 ) Pub Date : 2019-09-30 , DOI: 10.1111/febs.15075
Tohidul Islam 1 , Anna L Gharibyan 1 , Solmaz A Golchin 1 , Nina Pettersson 1 , Kristoffer Brännström 1 , Isabell Hedberg 1 , Merit-Miriam Virta 1 , Linnea Olofsson 1 , Anders Olofsson 1
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Alzheimer's disease (AD) is strongly linked to amyloid depositions of the Aβ peptide (Aβ). The lipid-binding protein apolipoprotein E (ApoE) has been found to interfere with Aβ amyloid formation and to exert a strong clinical impact to the pathology of AD. The APOE gene exists in three allelic isoforms represented by APOE ε2, APOE ε3, and APOE ε4. Carriers of the APOE ε4 variant display a gene dose-dependent increased risk of developing the disease. Aβ amyloids are formed via a nucleation-dependent mechanism where free monomers are added onto a nucleus in a template-dependent manner. Using a combination of surface plasmon resonance and thioflavin-T assays, we here show that ApoE can target the process of fibril elongation and that its interference effectively prevents amyloid maturation. We expose a complex equilibrium where the concentration of ApoE, Aβ monomers, and the amount of already formed Aβ fibrils will affect the relative proportion and formation rate of mature amyloids versus alternative assemblies. The result illustrates a mechanism which may affect both the clearance rate of Aβ assemblies in vivo and the population of cytotoxic Aβ assemblies.

中文翻译:

载脂蛋白E损害淀粉样蛋白β原纤维的伸长和成熟。

阿尔茨海默氏病(AD)与Aβ肽(Aβ)的淀粉样蛋白沉积密切相关。已经发现脂质结合蛋白载脂蛋白E(ApoE)会干扰Aβ淀粉样蛋白的形成并对AD的病理学产生强烈的临床影响。APOE基因以APOEε2,APOEε3和APOEε4代表的三个等位基因亚型存在。APOEε4变体的携带者表现出基因剂量依赖性增加罹患该疾病的风险。Aβ淀粉样蛋白通过成核依赖性机制形成,其中将游离单体以模板依赖性方式添加到细胞核上。使用表面等离振子共振和硫代黄素-T分析相结合,我们在这里表明ApoE可以靶向原纤维延长的过程,并且其干扰有效地阻止了淀粉样蛋白的成熟。我们揭示了一个复杂的平衡点,其中ApoE,Aβ单体的浓度以及已经形成的Aβ原纤维的量将影响成熟淀粉样蛋白相对于替代组装的相对比例和形成速率。该结果说明了可能影响体内Aβ装配体的清除率和细胞毒性Aβ装配体群体的机制。
更新日期:2020-03-16
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