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Abstract：
Docosahexaenoic acid (DHA, C22:6 ω3) may be involved in various neuroprotective mechanisms that could prevent Alzheimer\'s disease (AD). Its influence has still been little explored regarding the dysfunction of the endolysosomal pathway, known as an early key event in the physiopathological continuum triggering AD. This dysfunction could result from the accumulation of degradation products of the precursor protein of AD, in particular the C99 fragment, capable of interacting with endosomal proteins and thus contributing to altering this pathway from the early stages of AD. This study aims to evaluate whether neuroprotection mediated by DHA can also preserve the endolysosomal function. AD-typical endolysosomal abnormalities were recorded in differentiated human SH-SY5Y neuroblastoma cells expressing the Swedish form of human amyloid precursor protein. This altered phenotype included endosome enlargement, the reduced secretion of exosomes, and a higher level of apoptosis, which confirmed the relevance of the cellular model chosen for studying the associated deleterious mechanisms. Second, neuroprotection mediated by DHA was associated with a reduced interaction of C99 with the Rab5 GTPase, lower endosome size, restored exosome production, and reduced neuronal apoptosis. Our data reveal that DHA may influence protein localization and interactions in the neuronal membrane environment, thereby correcting the dysfunction of endocytosis and vesicular trafficking associated with AD.
摘要：
二十二碳六烯酸（DHA，C22：6ω3）可能参与可以预防阿尔茨海默病（AD）的各种神经保护机制。关于内溶酶体途径的功能障碍，它的影响还很少被探索，被称为生理病理连续体触发AD的早期关键事件。这种功能障碍可能是由于AD前体蛋白降解产物的积累，特别是C99片段,能够与内体蛋白相互作用，从而有助于从AD的早期阶段改变该途径。这项研究旨在评估DHA介导的神经保护是否也可以保留内溶酶体功能。在表达瑞典形式的人淀粉样前体蛋白的分化的人SH-SY5Y神经母细胞瘤细胞中记录了AD典型的内溶酶体异常。这种改变的表型包括内体扩大，外泌体分泌减少，和更高水平的细胞凋亡，这证实了选择用于研究相关有害机制的细胞模型的相关性。第二,由DHA介导的神经保护与C99与Rab5GTP酶的相互作用减少有关，较低的内体大小，恢复了外泌体的生产，减少神经元凋亡。我们的数据表明，DHA可能会影响神经元膜环境中的蛋白质定位和相互作用，从而纠正与AD相关的内吞和囊泡运输的功能障碍。
