Monteiro-Cardoso Vera F, Oliveira M Manuel, Melo Tânia, Domingues Maria R M, Moreira Paula I, Ferreiro Elisabete, Peixoto Francisco, Videira Romeu A
Chemistry Center - Vila Real (CQ-VR), Chemistry Department, School of Life and Environmental Sciences, University of Trás-os-Montes e Alto Douro, UTAD, Vila Real, Portugal.
Mass Spectrometry Center, UI-QOPNA, Chemistry Department, University of Aveiro, Aveiro, Portugal.
J Alzheimers Dis. 2015;43(4):1375-92. doi: 10.3233/JAD-141002.
Brain mitochondria are fundamental to maintaining healthy functional brains, and their dysfunction is involved in age-related neurodegenerative disorders such as Alzheimer's disease (AD). In this study, we conducted a research on how both non-synaptic and synaptic mitochondrial functions are compromised at an early stage of AD-like pathologies and their correlation with putative changes on membranes lipid profile, using 3 month-old nontransgenic and 3xTg-AD mice, a murine model of experimental AD. Bioenergetic dysfunction in 3xTg-AD brains is evidenced by a decrease of brain ATP levels resulting, essentially, from synaptic mitochondria functionality disruption as indicated by declined respiratory control ratio associated with a 50% decreased complex I activity. Lipidomics studies revealed that synaptic bioenergetic deficit of 3xTg-AD brains is accompanied by alterations in the phospholipid composition of synaptic mitochondrial membranes, detected either in phospholipid class distribution or in the phospholipids molecular profile. Globally, diacyl- and lyso-phosphatidylcholine lipids increase while ethanolamine plasmalogens and cardiolipins content drops in relation to nontransgenic background. However, the main lipidomic mark of 3xTg-AD brains is that cardiolipin cluster-organized profile is lost in synaptic mitochondria due to a decline of the most representative molecular species. In contrast to synaptic mitochondria, results support the idea that non-synaptic mitochondria function is preserved at the age of 3 months. Although the genetically construed 3xTg-AD mouse model does not represent the most prevalent form of AD in humans, the present study provides insights into the earliest biochemical events in AD brain, connecting specific lipidomic changes with synaptic bioenergetic deficit that may contribute to the progressive synapses loss and the neurodegenerative process that characterizes AD.
脑线粒体对于维持健康的功能性大脑至关重要，其功能障碍与年龄相关的神经退行性疾病如阿尔茨海默病（AD）有关。在本研究中，我们使用3个月大的非转基因小鼠和3xTg-AD小鼠（一种实验性AD的小鼠模型），研究了在AD样病理早期非突触和突触线粒体功能如何受损，以及它们与膜脂质谱假定变化的相关性。3xTg-AD大脑中的生物能量功能障碍表现为脑ATP水平降低，这主要是由于突触线粒体功能破坏所致，如呼吸控制率下降以及复合体I活性降低50%所表明的。脂质组学研究表明，3xTg-AD大脑的突触生物能量缺陷伴随着突触线粒体膜磷脂组成的改变，这在磷脂类分布或磷脂分子谱中均有检测到。总体而言，与非转基因背景相比，二酰基和溶血磷脂酰胆碱脂质增加，而乙醇胺缩醛磷脂和心磷脂含量下降。然而，3xTg-AD大脑的主要脂质组学特征是，由于最具代表性的分子种类减少，突触线粒体中的心磷脂簇组织谱消失。与突触线粒体不同，结果支持在3个月大时非突触线粒体功能得以保留的观点。尽管基因构建的3xTg-AD小鼠模型并不代表人类中最普遍的AD形式，但本研究为AD大脑中最早的生化事件提供了见解，将特定的脂质组学变化与突触生物能量缺陷联系起来，这可能导致渐进性突触丧失和AD特有的神经退行性过程。
