Department of Pharmacology and Toxicology, University of Navarra, Pamplona, Spain.
Centre for Nutrition Research, University of Navarra, Pamplona, Spain.
Mol Neurobiol. 2019 Mar;56(3):1618-1627. doi: 10.1007/s12035-018-1185-7. Epub 2018 Jun 17.
A potential role of marine n-3 polyunsaturated fatty acids (ω-3 PUFAs) has been suggested in memory, learning, and cognitive processes. Therefore, ω-3 PUFAs might be a promising treatment option, albeit controversial, for Alzheimer's disease (AD). Among the different mechanisms that have been proposed as responsible for the beneficial effects of ω-3 PUFAs, inhibition of JNK stands as a particularly interesting candidate. In the present work, it has been studied whether the administration of two different PUFAs (docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA)) and a DHA-derived specialized pro-resolving lipid mediator (MaR1) is able to reverse cognitive deficits in the senescence-accelerated mouse prone 8 (SAMP8) mouse model of sporadic AD. The novel object recognition test (NORT) test showed that recognition memory was significantly impaired in SAMP8 mice, as shown by a significantly decreased discrimination index that was reversed by MaR1 and DHA. In the retention phase of the Morris water maze (MWM) task, SAMP8 mice showed memory deficit that only DHA treatment was able to reverse. pJNK levels were significantly increased in the hippocampus of SAMP8 mice compared to SAMR1 mice, and only DHA treatment was able to significantly reverse these increased pJNK levels. Similar results were found when measuring c-Jun, the main JNK substrate. Consequently to the increases in tau phosphorylation after increased pJNK, it was checked that tau phosphorylation (PHF-1) was increased in SAMP mice, and this effect was reversed after DHA treatment. Altogether, DHA could represent a new approach for the treatment of AD through JNK inhibition.
海洋 n-3 多不饱和脂肪酸（ω-3PUFAs）在记忆、学习和认知过程中可能发挥作用。因此，ω-3PUFAs 可能是一种有前途的治疗阿尔茨海默病（AD）的方法，尽管存在争议。在被认为是 ω-3PUFAs 有益作用的不同机制中，抑制 JNK 是一个特别有趣的候选机制。在本研究中，研究了两种不同的 PUFAs（二十二碳六烯酸（DHA）和二十碳五烯酸（EPA））和一种 DHA 衍生的专门促解决的脂质介质（MaR1）的给药是否能够逆转散发性 AD 的衰老加速型小鼠易患 8 号（SAMP8）小鼠模型的认知缺陷。新物体识别测试（NORT）表明，SAMP8 小鼠的识别记忆明显受损，表现为辨别指数显著降低，而 MaR1 和 DHA 可逆转这种降低。在 Morris 水迷宫（MWM）任务的保留阶段，SAMP8 小鼠表现出记忆缺陷，只有 DHA 处理才能逆转。与 SAMR1 小鼠相比，SAMP8 小鼠海马中的 pJNK 水平显著升高，只有 DHA 处理才能显著逆转这些升高的 pJNK 水平。当测量 JNK 的主要底物 c-Jun 时，发现了类似的结果。由于 pJNK 增加导致 tau 磷酸化增加，因此检查了 SAMP 小鼠中 tau 磷酸化（PHF-1）增加，并且 DHA 处理可逆转这种作用。总之，DHA 可通过抑制 JNK 成为治疗 AD 的新方法。
