The use of fixed fibroblasts from familial and sporadic Alzheimer's disease patients has previously indicated an upregulation of mitochondria-ER contacts (MERCs) as a hallmark of Alzheimer's disease. Despite its potential significance, the relevance of these results is limited because they were not extended to live neurons. Here we performed a dynamic in vivo analysis of MERCs in hippocampal neurons from McGill-R-Thy1-APP transgenic rats, a model of Alzheimer's disease-like amyloid pathology. Live FRET imaging of neurons from transgenic rats revealed perturbed 'lipid-MERCs' (gap width <10 nm), while 'Ca2+-MERCs' (10-20 nm gap width) were unchanged. In situ TEM showed no significant differences in the lipid-MERCs:total MERCs or lipid-MERCs:mitochondria ratios; however, the average length of lipid-MERCs was significantly decreased in neurons from transgenic rats as compared to controls. In accordance with FRET results, untargeted lipidomics showed significant decreases in levels of 12 lipids and bioenergetic analysis revealed respiratory dysfunction of mitochondria from transgenic rats. Thus, our results reveal changes in MERC structures coupled with impaired mitochondrial functions in Alzheimer's disease-related neurons.This article has an associated First Person interview with the first author of the paper.

中文翻译：

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活的神经元中的线粒体-ER接触紊乱，可模拟阿尔茨海默氏病的淀粉样蛋白病理。

以前，使用家族性和散发性阿尔茨海默氏病患者的固定成纤维细胞已表明，线粒体-ER接触（MERCs）的上调是阿尔茨海默氏病的标志。尽管其潜在的意义，但这些结果的相关性是有限的，因为它们没有扩展到活的神经元。在这里，我们对McGill-R-Thy1-APP转基因大鼠（一种阿尔茨海默氏病样淀粉样蛋白病理模型）的海马神经元进行了MERC的动态体内分析。来自转基因大鼠的神经元的实时FRET成像显示扰动的“脂质-MERCs”（间隙宽度<10 nm），而“ Ca2 + -MERCs”（10-20 nm间隙宽度）未发生变化。原位透射电镜显示脂质-MERCs：总MERCs或脂质-MERCs：线粒体比率没有显着差异；然而，与对照组相比，转基因大鼠神经元中脂质-MERC的平均长度显着减少。根据FRET结果，未靶向的脂质组学显示12种脂质的水平显着降低，生物能分析表明转基因大鼠的线粒体呼吸功能异常。因此，我们的结果揭示了阿尔茨海默氏病相关神经元中MERC结构的变化以及线粒体功能受损。