Torres Manuel, Price Samantha L, Fiol-Deroque Maria A, Marcilla-Etxenike Amaia, Ahyayauch Hasna, Barceló-Coblijn Gwendolyn, Terés Silvia, Katsouri Loukia, Ordinas Margarita, López David J, Ibarguren Maitane, Goñi Félix M, Busquets Xavier, Vitorica Javier, Sastre Magdalena, Escribá Pablo V
Laboratory of Molecular Cell Biomedicine, University of the Balearic Islands, Palma de Mallorca, Spain.
Division of Brain Sciences, Imperial College London, London, United Kingdom.
Biochim Biophys Acta. 2014 Jun;1838(6):1680-92. doi: 10.1016/j.bbamem.2013.12.016. Epub 2013 Dec 27.
Alzheimer's disease (AD) is a neurodegenerative pathology with relevant unmet therapeutic needs. Both natural aging and AD have been associated with a significant decline in the omega-3 polyunsaturated fatty acid docosahexaenoic acid (DHA), and accordingly, administration of DHA has been proposed as a possible treatment for this pathology. However, recent clinical trials in mild-to-moderately affected patients have been inconclusive regarding the real efficacy of DHA in halting this disease. Here, we show that the novel hydroxyl-derivative of DHA (2-hydroxydocosahexaenoic acid - OHDHA) has a strong therapeutic potential to treat AD. We demonstrate that OHDHA administration increases DHA levels in the brain of a transgenic mouse model of AD (5xFAD), as well as those of phosphatidylethanolamine (PE) species that carry long polyunsaturated fatty acids (PUFAs). In 5xFAD mice, administration of OHDHA induced lipid modifications that were paralleled with a reduction in amyloid-β (Αβ) accumulation and full recovery of cognitive scores. OHDHA administration also reduced Aβ levels in cellular models of AD, in association with alterations in the subcellular distribution of secretases and reduced Aβ-induced tau protein phosphorylation as well. Furthermore, OHDHA enhanced the survival of neuron-like differentiated cells exposed to different insults, such as oligomeric Aβ and NMDA-mediated neurotoxicity. These results were supported by model membrane studies in which incorporation of OHDHA into lipid-raft-like vesicles was shown to reduce the binding affinity of oligomeric and fibrillar Aβ to membranes. Finally, the OHDHA concentrations used here did not produce relevant toxicity in zebrafish embryos in vivo. In conclusion, we demonstrate the pleitropic effects of OHDHA that might prove beneficial to treat AD, which suggests that an upstream event, probably the modulation of the membrane lipid composition and structure, influences cellular homeostasis reversing the neurodegenerative process. This Article is Part of a Special Issue Entitled: Membrane Structure and Function: Relevance in the Cell's Physiology, Pathology and Therapy.
阿尔茨海默病（AD）是一种存在相关未满足治疗需求的神经退行性病变。自然衰老和AD均与ω-3多不饱和脂肪酸二十二碳六烯酸（DHA）的显著下降有关，因此，已有人提出给予DHA作为治疗这种病变的一种可能方法。然而，最近针对轻度至中度受影响患者的临床试验对于DHA在阻止这种疾病方面的实际疗效尚无定论。在此，我们表明DHA的新型羟基衍生物（2-羟基二十二碳六烯酸 - OHDHA）具有治疗AD的强大治疗潜力。我们证明给予OHDHA可提高AD转基因小鼠模型（5xFAD）大脑中的DHA水平，以及携带长链多不饱和脂肪酸（PUFA）的磷脂酰乙醇胺（PE）种类的水平。在5xFAD小鼠中，给予OHDHA诱导脂质修饰，同时淀粉样β蛋白（Αβ）积累减少且认知评分完全恢复。给予OHDHA还降低了AD细胞模型中的Aβ水平，这与分泌酶亚细胞分布的改变以及Aβ诱导的tau蛋白磷酸化减少有关。此外，OHDHA提高了暴露于不同损伤（如寡聚Aβ和NMDA介导的神经毒性）的神经元样分化细胞的存活率。这些结果得到了模型膜研究的支持，其中显示将OHDHA掺入类脂筏小泡可降低寡聚和纤维状Aβ与膜的结合亲和力。最后，此处使用的OHDHA浓度在体内对斑马鱼胚胎未产生相关毒性。总之，我们证明了OHDHA的多效性作用可能对治疗AD有益，这表明一个上游事件，可能是膜脂质组成和结构的调节，影响细胞内稳态并逆转神经退行性过程。本文是名为：膜结构与功能：在细胞生理学、病理学和治疗中的相关性的特刊的一部分。
