title: Cardiolipin profile changes are associated to the early synaptic mitochondrial dysfunction in Alzheimer's disease.
abstract: 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.
authors.affiliation: 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.
authors.forename: Vera F
authors.initials: VF
authors.lastname: Monteiro-Cardoso
authors.affiliation: 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.
authors.forename: M Manuel
authors.initials: MM
authors.lastname: Oliveira
authors.affiliation: Mass Spectrometry Center, UI-QOPNA, Chemistry Department, University of Aveiro, Aveiro, Portugal.
authors.forename: Tânia
authors.initials: T
authors.lastname: Melo
authors.affiliation: Mass Spectrometry Center, UI-QOPNA, Chemistry Department, University of Aveiro, Aveiro, Portugal.
authors.forename: Maria R M
authors.initials: MR
authors.lastname: Domingues
authors.affiliation: Laboratory of Physiology, Faculty of Medicine, University of Coimbra, Coimbra, Portugal CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
authors.forename: Paula I
authors.initials: PI
authors.lastname: Moreira
authors.affiliation: CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal Institute for Interdisciplinary Research (IIIUC), University of Coimbra, Coimbra, Portugal.
authors.forename: Elisabete
authors.initials: E
authors.lastname: Ferreiro
authors.affiliation: Centre for the Research and Technology of Agro-Environmental and Biological Sciences (CITAB), Department of Biology and Environment, School of Life and Environmental Sciences, UTAD, Vila Real, Portugal.
authors.forename: Francisco
authors.initials: F
authors.lastname: Peixoto
authors.affiliation: 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.
authors.forename: Romeu A
authors.initials: RA
authors.lastname: Videira
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000544:Alzheimer Disease / Q000473:pathology / Q000503:physiopathology*; D000818:Animals; D001921:Brain / Q000473:pathology / Q000503:physiopathology*; D002308:Cardiolipins / Q000378:metabolism*; D004195:Disease Models, Animal; D042967:Electron Transport Complex I / Q000378:metabolism; D008297:Male; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008928:Mitochondria / Q000502:physiology*; D051336:Mitochondrial Membranes / Q000378:metabolism; D010743:Phospholipids / Q000378:metabolism; D010766:Phosphorylation; D013569:Synapses / Q000502:physiology*
chemical_list: D002308:Cardiolipins; D010743:Phospholipids; D000255:Adenosine Triphosphate; D055372:AMP-Activated Protein Kinases; D042967:Electron Transport Complex I
keywords: Alzheimer's disease; brain bioenergetics; cardiolipin; mitochondrial lipidomics