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Differential Lipid Mediator Involvement in the Different Forms of Genetic Frontotemporal Dementia: Novel Insights into Neuroinflammation
Journal of Alzheimer’s Disease ( IF 4 ) Pub Date : 2021-09-15 , DOI: 10.3233/jad-210559
Aitana Sogorb-Esteve 1, 2 , Romain A Colas 3 , Jesmond Dalli 3, 4 , Jonathan D Rohrer 2
Affiliation  

Background:The pathophysiology of frontotemporal dementia (FTD) is poorly understood but recent studies implicate neuroinflammation as an important factor. However, little is known so far about the role of the resolution pathway, the response to inflammation that allows tissue to return to a homeostatic state. Objective:We aimed to measure the concentrations of lipid mediators including specialized proresolving mediators (SPMs) and proinflammatory eicosanoids in the cerebrospinal fluid (CSF) of people with FTD. Methods:15 people with genetic FTD (5 with C9orf72 expansions, 5 with GRN mutations, and 5 with MAPT mutations) were recruited to the study along with 15 age- and sex-matched healthy controls. Targeted liquid chromatography-tandem mass spectrometry techniques were used to measure the CSF concentrations of lipid mediators in the docosahexaenoic acid (DHA), n-3 docosapentaenoic acid, eicosapentaenoic acid, and arachidonic acid (AA) metabolomes. Results:Only the C9orf72 expansion carriers had higher concentrations of SPMs (DHA-derived maresins and DHA-derived resolvins) compared with controls. In contrast, GRN and MAPT mutation carriers had normal concentrations of SPMs but significantly higher concentrations of the proinflammatory AA-derived leukotrienes and AA-derived thromboxane compared with controls. Additionally, the C9orf72 expansion carriers also had significantly higher concentrations of AA-derived leukotrienes. Conclusion:This initial pilot study of lipid mediators provides a window into a novel biological pathway not previously investigated in FTD, showing differential patterns of alterations between those with C9orf72 expansions (where SPMs are higher) and GRN and MAPT mutations (where only proinflammatory eicosanoids are higher).

中文翻译:

不同形式的遗传性额颞叶痴呆中的差异脂质介质参与:对神经炎症的新见解

背景:额颞叶痴呆 (FTD) 的病理生理学知之甚少,但最近的研究表明神经炎症是一个重要因素。然而,到目前为止,关于消退途径的作用知之甚少,即对炎症的反应使组织恢复到稳态。目的:我们旨在测量 FTD 患者脑脊液 (CSF) 中脂质介质的浓度,包括专门的促分解介质 (SPM) 和促炎类花生酸。方法:15 名患有遗传性 FTD 的人(5 名具有 C9orf72 扩增,5 名具有 GRN 突变,5 名具有 MAPT 突变)与 15 名年龄和性别匹配的健康对照一起被招募到研究中。靶向液相色谱-串联质谱技术用于测量二十二碳六烯酸 (DHA)、n-3 二十二碳五烯酸、二十碳五烯酸和花生四烯酸 (AA) 代谢组中脂质介质的脑脊液浓度。结果:与对照组相比,只有 C9orf72 扩增载体具有更高浓度的 SPM(DHA 衍生的 maresins 和 DHA 衍生的 resolvins)。相比之下,与对照组相比,GRN 和 MAPT 突变携带者的 SPM 浓度正常,但促炎 AA 衍生的白三烯和 AA 衍生的血栓素浓度显着升高。此外,C9orf72 扩增载体还具有明显更高浓度的 AA 衍生白三烯。结论:
更新日期:2021-09-17
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