The Novel Omega-6 Fatty Acid Docosapentaenoic Acid Positively Modulates Brain Innate Immune Response for Resolving Neuroinflammation at Early and Late Stages of Humanized APOE-Based Alzheimer's Disease Models.
The Novel Omega-6 Fatty Acid Docosapentaenoic Acid Positively Modulates Brain Innate Immune Response for Resolving Neuroinflammation at Early and Late Stages of Humanized APOE-Based Alzheimer's Disease Models.
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DOI：
10.3389/fimmu.2020.558036
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发表时间：
2020
影响因子：
7.3
通讯作者：
Cole GM
中科院分区：
文献类型：
--
作者：
Ma QL;Zhu C;Morselli M;Su T;Pelligrini M;Lu Z;Jones M;Denver P;Castro D;Gu X;Relampagos F;Caoili K;Teter B;Frautschy SA;Cole GM
神经炎症在阿尔茨海默病 (AD) 的发生和进展中起着至关重要的作用，其中激活的小胶质细胞被发现与神经退行性疾病相关。然而，有限的证据表明神经炎症和激活的小胶质细胞如何与体内神经变性直接相关。此外，目前还没有针对AD的有效抗炎药物。在这项研究中，我们报告了一种有效的抗炎脂质、亚油酸 (LA) 代谢物二十二碳五烯酸 (DPAn-6) 治疗患有晚期 AD 病理的老年人源化 EFAD 小鼠。我们还报告了神经炎症和/或激活的小胶质细胞标记物与体内神经变性的关联。首先，我们发现，在成年 AD 模型 E3FAD 和 E4FAD 小鼠中，膳食 LA 减少了 IL1-β、IL-6 的促炎细胞因子以及 COX2 的 mRNA 表达，从而通过增加 IL-10 来解决神经炎症。脑脂肪酸测定显示，与标准饮食相比，膳食 LA 使 DPAn-6 增加了 5 至 6 倍，尤其是 E4FAD 小鼠。因此，我们在老年 E4FAD 小鼠中测试了 DPAn-6。通过口服管饲法将 DPAn-6 给予 E4FAD 小鼠三周后，我们发现 DPAn-6 减少了小胶质细胞增生以及炎症、小胶质细胞和 caspase 标记物的 mRNA 表达。此外，DPAn-6 同时增加 ADCYAP1、VGF 和神经元五聚蛋白 2 的 mRNA 表达，所有这些都与炎症和小胶质细胞标志物呈负相关。最后，LA 和 DPAn-6 均直接降低淀粉样蛋白-β42 寡聚物攻击的 BV2 小胶质细胞中 COX2 的 mRNA 表达。总之，这些数据表明 DPAn-6 调节神经炎症反应，以解决和改善 AD 模型晚期的神经变性。
Neuroinflammation plays a crucial role in the development and progression of Alzheimer's disease (AD), in which activated microglia are found to be associated with neurodegeneration. However, there is limited evidence showing how neuroinflammation and activated microglia are directly linked to neurodegeneration in vivo. Besides, there are currently no effective anti-inflammatory drugs for AD. In this study, we report on an effective anti-inflammatory lipid, linoleic acid (LA) metabolite docosapentaenoic acid (DPAn-6) treatment of aged humanized EFAD mice with advanced AD pathology. We also report the associations of neuroinflammatory and/or activated microglial markers with neurodegeneration in vivo. First, we found that dietary LA reduced proinflammatory cytokines of IL1-β, IL-6, as well as mRNA expression of COX2 toward resolving neuroinflammation with an increase of IL-10 in adult AD models E3FAD and E4FAD mice. Brain fatty acid assays showed a five to six-fold increase in DPAn-6 by dietary LA, especially more in E4FAD mice, when compared to standard diet. Thus, we tested DPAn-6 in aged E4FAD mice. After DPAn-6 was administered to the E4FAD mice by oral gavage for three weeks, we found that DPAn-6 reduced microgliosis and mRNA expressions of inflammatory, microglial, and caspase markers. Further, DPAn-6 increased mRNA expressions of ADCYAP1, VGF, and neuronal pentraxin 2 in parallel, all of which were inversely correlated with inflammatory and microglial markers. Finally, both LA and DPAn-6 directly reduced mRNA expression of COX2 in amyloid-beta42 oligomer-challenged BV2 microglial cells. Together, these data indicated that DPAn-6 modulated neuroinflammatory responses toward resolution and improvement of neurodegeneration in the late stages of AD models.
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DOI：
10.1056/nejmoa1211851
发表时间：
2013-01-10
期刊：
The New England journal of medicine
影响因子：
--
作者：
Guerreiro R;Wojtas A;Bras J;Carrasquillo M;Rogaeva E;Majounie E;Cruchaga C;Sassi C;Kauwe JS;Younkin S;Hazrati L;Collinge J;Pocock J;Lashley T;Williams J;Lambert JC;Amouyel P;Goate A;Rademakers R;Morgan K;Powell J;St George-Hyslop P;Singleton A;Hardy J;Alzheimer Genetic Analysis Group
通讯作者：
Alzheimer Genetic Analysis Group
影响因子：
9.3
作者：
Cribbs DH;Berchtold NC;Perreau V;Coleman PD;Rogers J;Tenner AJ;Cotman CW
通讯作者：
Cotman CW
影响因子：
3.7
作者：
Costa-Silva J;Domingues D;Lopes FM
通讯作者：
Lopes FM
DOI：
10.1186/s13195-017-0335-x
发表时间：
2018-01-15
期刊：
Alzheimer's research & therapy
影响因子：
--
作者：
Duits FH;Brinkmalm G;Teunissen CE;Brinkmalm A;Scheltens P;Van der Flier WM;Zetterberg H;Blennow K
通讯作者：
Blennow K
影响因子：
5.3
作者：
Bolmont, Tristan;Haiss, Florent;Calhoun, Michael E.
通讯作者：
Calhoun, Michael E.