Sharma Neha, Baek KeangOK, Phan Huong T T, Shimokawa Naofumi, Takagi Masahiro
School of Materials Science Japan Advanced Institute of Science and Technology (JAIST) Ishikawa Japan.
Hanoi National University of Education Caugiay Vietnam.
FEBS Open Bio. 2017 May 18;7(6):865-876. doi: 10.1002/2211-5463.12234. eCollection 2017 Jun.
Amyloid beta (Aβ) is a peptide responsible for the development of Alzheimer's disease (AD). Misfolding and accumulation of endogenous Aβ can lead to neural cell apoptosis through endoplasmic reticulum (ER) stress. Added exogenous Aβ can also result in ER stress, leading to neurotoxicity and apoptosis, which is identical to that caused by the endogenous peptide. We have speculated that the endocytic transport of Aβ causes ER stress and have previously shown that the oxysterol, in particular, 7-ketocholesterol (7-keto) induces more surface interaction between Aβ-42 and Jurkat cells than cholesterol. However, the interaction was not enough to induce intracellular transfer of the peptide. In this study, we investigated the effect of another oxysterol, 25-hydroxycholesterol (25-OH) on the membrane raft-dependent transport of Aβ-42 in Jurkat cells. Interestingly, intracellular transfer of Aβ-42 was observed in the presence of 25-OH only after the inclusion of cholera toxin B subunit (CT-B), a marker used to detect the raft domain. We speculated that 25-OH can induce intracellular movement of Aβ peptides. Furthermore, CT-B together with GM1 provided negative curvature, which resulted in the intracellular transport of Aβ-42. Notably, we used a protofibrillar species of Aβ-42 in this study. We have shown that the transport was microtubule-dependent since it could not be observed in depolymerized microtubules. These results demonstrate that oxysterols and glycosyl chains are important factors affecting intracellular transport. These compounds are also associated with aging and advanced glycation are risk factors for AD. Thus, this study should further understanding of the pathology of AD.
β淀粉样蛋白（Aβ）是一种与阿尔茨海默病（AD）发病相关的肽。内源性Aβ的错误折叠和积累可通过内质网（ER）应激导致神经细胞凋亡。添加外源性Aβ也会导致内质网应激，进而引起神经毒性和细胞凋亡，这与内源性肽所导致的情况相同。我们推测Aβ的内吞转运导致内质网应激，并且此前已表明，氧化甾醇，特别是7-酮胆固醇（7-keto）比胆固醇能诱导更多Aβ-42与Jurkat细胞之间的表面相互作用。然而，这种相互作用不足以诱导该肽的细胞内转运。在本研究中，我们研究了另一种氧化甾醇25-羟基胆固醇（25-OH）对Jurkat细胞中Aβ-42膜筏依赖性转运的影响。有趣的是，仅在加入霍乱毒素B亚基（CT-B）（一种用于检测筏域的标志物）后，在25-OH存在的情况下才观察到Aβ-42的细胞内转运。我们推测25-OH可诱导Aβ肽的细胞内移动。此外，CT-B与GM1一起提供了负曲率，这导致了Aβ-42的细胞内转运。值得注意的是，在本研究中我们使用的是Aβ-42的原纤维形式。我们已经表明这种转运是微管依赖性的，因为在解聚的微管中未观察到这种转运。这些结果表明氧化甾醇和糖基链是影响细胞内转运的重要因素。这些化合物也与衰老相关，而晚期糖基化是AD的危险因素。因此，本研究应有助于进一步了解AD的病理学。
