Human apolipoprotein E isoforms are differentially sialylated and the sialic acid moiety in ApoE2 attenuates ApoE2-Aβ interaction and Aβ fibrillation.
Human apolipoprotein E isoforms are differentially sialylated and the sialic acid moiety in ApoE2 attenuates ApoE2-Aβ interaction and Aβ fibrillation.
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DOI：
10.1016/j.nbd.2022.105631
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发表时间：
2022-03
影响因子：
6.1
通讯作者：
Zhao, Liqin
中科院分区：
文献类型：
--
作者：
Moon, Hee-Jung;Haroutunian, Vahram;Zhao, Liqin
关键词：
APOE基因型是迟发性阿尔茨海默病（late-onset Alzheimer 's disease， LOAD）发生最显著的遗传危险因素；然而，潜在的机制仍不清楚。在本研究中，我们发现ApoE蛋白在人脑中的唾液酸修饰谱在三种亚型之间存在显著差异，其中ApoE2表现出最丰富的唾液酸修饰，而ApoE4则最少。我们进一步观察到，ApoE2中的唾液酸片段显著影响ApoE2与Aβ肽的相互作用。ApoE2中唾液酸的去除增加了ApoE2对Aβ的Aβ17-24区的结合亲和力，促进了Aβ的纤颤。这些发现为ApoE亚型在a β发病机制中的不同作用提供了合理的解释。具体来说，与其他两种同型相比，ApoE2中唾液酸的高表达可能导致ApoE2与a β之间的相互作用减弱，最终导致脑内a β沉积速度减慢，这一机制被认为是ApoE2介导的AD风险降低的基础。未来的研究有必要确定ApoE亚型的唾液化差异是否也可能有助于它们的一些其他独特特性，例如它们与脂质和脂蛋白相关的不同偏好，以及它们通过调节小胶质Siglec活性对神经炎症的潜在影响。总的来说，我们的研究结果揭示了唾液酸结构是一个重要的翻译后修饰（PTM），它改变了ApoE蛋白与AD相关的功能。
The APOE genotype is the most prominent genetic risk factor for the development of late-onset Alzheimer’s disease (LOAD); however, the underlying mechanisms remain unclear. In the present study, we found that the sialylation profiles of ApoE protein in the human brain are significantly different among the three isoforms, with ApoE2 exhibiting the most abundant sialic acid modification whereas ApoE4 had the least. We further observed that the sialic acid moiety in ApoE2 significantly affected the interaction between ApoE2 and Aβ peptides. The removal of sialic acid in ApoE2 increased the ApoE2 binding affinity for the Aβ17-24 region of Aβ and promoted Aβ fibrillation. These findings provide a plausible explanation for the well-documented differential roles of ApoE isoforms in Aβ pathogenesis. Specifically, compared to the other two isotypes, the higher expression of sialic acid in ApoE2 may contribute to the less potent interaction between ApoE2 and Aβ and ultimately the slower rate of brain Aβ deposition, a mechanism thought to underlie ApoE2-mediated decreased risk for AD. Future studies are warranted to determine whether the differential sialylation in ApoE isoforms may also contribute to some of their other distinct properties, such as their divergent preferences in associations with lipids and lipoproteins, as well as their potential impact on neuroinflammation through modulation of microglial Siglec activity. Overall, our findings lead to the insight that the sialic acid structure is an important posttranslational modification (PTM) that alters ApoE protein functions with relevance for AD.
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影响因子：
29
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通讯作者：
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影响因子：
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作者：
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通讯作者：
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