title: Graded perturbations of metabolism in multiple regions of human brain in Alzheimer's disease: Snapshot of a pervasive metabolic disorder.
abstract: Alzheimer's disease (AD) is an age-related neurodegenerative disorder that displays pathological characteristics including senile plaques and neurofibrillary tangles. Metabolic defects are also present in AD-brain: for example, signs of deficient cerebral glucose uptake may occur decades before onset of cognitive dysfunction and tissue damage. There have been few systematic studies of the metabolite content of AD human brain, possibly due to scarcity of high-quality brain tissue and/or lack of reliable experimental methodologies. Here we sought to: 1) elucidate the molecular basis of metabolic defects in human AD-brain; and 2) identify endogenous metabolites that might guide new approaches for therapeutic intervention, diagnosis or monitoring of AD. Brains were obtained from nine cases with confirmed clinical/neuropathological AD and nine controls matched for age, sex and post-mortem delay. Metabolite levels were measured in post-mortem tissue from seven regions: three that undergo severe neuronal damage (hippocampus, entorhinal cortex and middle-temporal gyrus); three less severely affected (cingulate gyrus, sensory cortex and motor cortex); and one (cerebellum) that is relatively spared. We report a total of 55 metabolites that were altered in at least one AD-brain region, with different regions showing alterations in between 16 and 33 metabolites. Overall, we detected prominent global alterations in metabolites from several pathways involved in glucose clearance/utilization, the urea cycle, and amino-acid metabolism. The finding that potentially toxigenic molecular perturbations are widespread throughout all brain regions including the cerebellum is consistent with a global brain disease process rather than a localized effect of AD on regional brain metabolism.
authors.affiliation: School of Biological Sciences, Faculty of Science and Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand; Centre for Brain Research, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand; Centre for Advanced Discovery and Experimental Therapeutics (CADET), Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Sciences Centre, Manchester, UK.
authors.forename: Jingshu
authors.initials: J
authors.lastname: Xu
authors.affiliation: Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK; Centre for Advanced Discovery and Experimental Therapeutics (CADET), Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Sciences Centre, Manchester, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Begley
authors.affiliation: Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK; Centre for Advanced Discovery and Experimental Therapeutics (CADET), Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Sciences Centre, Manchester, UK.
authors.forename: Stephanie J
authors.initials: SJ
authors.lastname: Church
authors.affiliation: School of Biological Sciences, Faculty of Science and Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand; Centre for Brain Research, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand; Centre for Advanced Discovery and Experimental Therapeutics (CADET), Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Sciences Centre, Manchester, UK.
authors.forename: Stefano
authors.initials: S
authors.lastname: Patassini
authors.affiliation: Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK; Centre for Advanced Discovery and Experimental Therapeutics (CADET), Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Sciences Centre, Manchester, UK.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Hollywood
authors.affiliation: School of Biological Sciences, Faculty of Science and Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand; Auckland Science Analytical Services, Faculty of Science, University of Auckland, Auckland, New Zealand.
authors.forename: Mia
authors.initials: M
authors.lastname: Jüllig
authors.affiliation: Centre for Brain Research, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
authors.forename: Maurice A
authors.initials: MA
authors.lastname: Curtis
authors.affiliation: Centre for Brain Research, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
authors.forename: Henry J
authors.initials: HJ
authors.lastname: Waldvogel
authors.affiliation: Centre for Brain Research, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
authors.forename: Richard L M
authors.initials: RL
authors.lastname: Faull
authors.affiliation: Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK; Centre for Advanced Discovery and Experimental Therapeutics (CADET), Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Sciences Centre, Manchester, UK.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Unwin
authors.affiliation: School of Biological Sciences, Faculty of Science and Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand; Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK; Centre for Brain Research, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand; Centre for Advanced Discovery and Experimental Therapeutics (CADET), Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Sciences Centre, Manchester, UK; Department of Pharmacology, Medical Sciences Division, University of Oxford, Oxford, UK. Electronic address: g.cooper@auckland.ac.nz.
authors.forename: Garth J S
authors.initials: GJ
authors.lastname: Cooper
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D000596:Amino Acids / Q000032:analysis / Q000378:metabolism; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D008297:Male; D053858:Metabolic Networks and Pathways; D055442:Metabolome; D055432:Metabolomics
chemical_list: D000596:Amino Acids
keywords: Alzheimer's disease; Brain amino-acid metabolism; Gas chromatography–mass spectrometry; Metabolic disorder; Metabolomics; Neurodegeneration