title: Unbiased Metabolomic Investigation of Alzheimer's Disease Brain Points to Dysregulation of Mitochondrial Aspartate Metabolism.
abstract: Alzheimer's disease (AD) is the most common cause of adult dementia. Yet the complete set of molecular changes accompanying this inexorable, neurodegenerative disease remains elusive. Here we adopted an unbiased lipidomics and metabolomics approach to surveying frozen frontal cortex samples from clinically characterized AD patients (n = 21) and age-matched controls (n = 19), revealing marked molecular differences between them. Then, by means of metabolomic pathway analysis, we incorporated the novel molecular information into the known biochemical pathways and compared it with the results of a metabolomics meta-analysis of previously published AD research. We found six metabolic pathways of the central metabolism as well as glycerophospholipid metabolism predominantly altered in AD brains. Using targeted metabolomics approaches and MS imaging, we confirmed a marked dysregulation of mitochondrial aspartate metabolism. The altered metabolic pathways were further integrated with clinical data, showing various degrees of correlation with parameters of dementia and AD pathology. Our study highlights specific, altered biochemical pathways in the brains of individuals with AD compared with those of control subjects, emphasizing dysregulation of mitochondrial aspartate metabolism and supporting future venues of investigation.
authors.affiliation: Center for Biomedicine, European Academy of Bolzano/Bozen , Via Galvani 31, 39100 Bolzano, Italy.|Center for Systems Biology, University of Iceland , Sturlugata 8, IS 101 Reykjavik, Iceland.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Paglia
authors.affiliation: S-IN Soluzioni Informatiche S.r.l. , via G. Ferrari 14, 36100 Vicenza, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Stocchero
authors.affiliation: Institute of Reproductive and Developmental Biology, Imperial College London , London SW7 2AZ, United Kingdom.
authors.forename: Stefano
authors.initials: S
authors.lastname: Cacciatore
authors.affiliation: Waters Corporation , Milford, Massachusetts 01757, United States.
authors.forename: Steven
authors.initials: S
authors.lastname: Lai
authors.affiliation: Protea Biosciences Group, Incorporated Morgantown, West Virginia 26505, United States.
authors.forename: Peggi
authors.initials: P
authors.lastname: Angel
authors.affiliation: Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge , 80 Tennis Court Road, Cambridge CB2 1GA, United Kingdom.
authors.forename: Mohammad Tauqeer
authors.initials: MT
authors.lastname: Alam
authors.affiliation: Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge , 80 Tennis Court Road, Cambridge CB2 1GA, United Kingdom.
authors.forename: Markus
authors.initials: M
authors.lastname: Keller
authors.affiliation: Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge , 80 Tennis Court Road, Cambridge CB2 1GA, United Kingdom.|Mill Hill Laboratory, The Francis Crick Institute , The Ridgeway, London NW1 7AA, United Kingdom.
authors.forename: Markus
authors.initials: M
authors.lastname: Ralser
authors.affiliation: Waters Corporation , Milford, Massachusetts 01757, United States.|Department of Biochemistry and Molecular & Cellular Biology, Georgetown University , Washington, District of Columbia 20007, United States.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Astarita
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism*; D001344:Autopsy; D001921:Brain / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D053858:Metabolic Networks and Pathways; D055442:Metabolome; D055432:Metabolomics / Q000379:methods*; D008928:Mitochondria / Q000378:metabolism*; D011180:Postmortem Changes; D021241:Spectrometry, Mass, Electrospray Ionization
keywords: Alzheimer’s disease; lipidomics; lipids; metabolic pathways; metabolomics