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Unbiased metabolomic investigation of Alzheimer's disease brain points to dysregulation of mitochondrial aspartate metabolism
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Paglia, Giuseppe, Stocchero, Matteo, Cacciatore, Stefano, Lai, Steven, Angel, Peggi, Alam, Mohammad T., Keller, Markus, Ralser, Markus and Astarita, Giuseppe (2016) Unbiased metabolomic investigation of Alzheimer's disease brain points to dysregulation of mitochondrial aspartate metabolism. Journal of Proteome Research, 15 (2). pp. 608-618.
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Official URL: http://dx.doi.org/10.1021/acs.jproteome.5b01020
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.
| Item Type: | Journal Article | ||||||||
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| Subjects: | R Medicine > RC Internal medicine | ||||||||
| Divisions: | Faculty of Medicine > Warwick Medical School > Biomedical Sciences > Cell & Developmental Biology Faculty of Medicine > Warwick Medical School > Biomedical Sciences Faculty of Medicine > Warwick Medical School |
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| Library of Congress Subject Headings (LCSH): | Alzheimer's disease, Nervous system -- Degeneration, Lipids -- Metabolism | ||||||||
| Journal or Publication Title: | Journal of Proteome Research | ||||||||
| Publisher: | American Chemical Society | ||||||||
| ISSN: | 1535-3893 | ||||||||
| Official Date: | 5 February 2016 | ||||||||
| Dates: |
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| Date of first compliant deposit: | 8 March 2017 | ||||||||
| Volume: | 15 | ||||||||
| Number: | 2 | ||||||||
| Page Range: | pp. 608-618 | ||||||||
| Status: | Peer Reviewed | ||||||||
| Publication Status: | Published | ||||||||
| Access rights to Published version: | Open Access | ||||||||
| Funder: | Alzheimer's Association, European Research Council (ERC), Wellcome Trust (London, England) | ||||||||
| Grant number: | NIRG-11-203674 (Alzheimer's Association), Grant 260809 (ERC), RG093735 (Wellcome Trust) |
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