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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. ISSN 1535-3893.

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Official URL: http://dx.doi.org/10.1021/acs.jproteome.5b01020

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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
Subjects: R Medicine > RC Internal medicine
Divisions: Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Biomedical Sciences > Cell & Developmental Biology
Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Biomedical Sciences
Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School
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:
DateEvent
5 February 2016Available
30 December 2015Accepted
3 November 2015Submitted
Volume: 15
Number: 2
Page Range: pp. 608-618
Status: Peer Reviewed
Publication Status: Published
Access rights to Published version: Open Access (Creative Commons)
Date of first compliant deposit: 8 March 2017
Date of first compliant Open Access: 8 March 2017
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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