期刊
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
卷 1862, 期 6, 页码 1084-1092出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbadis.2016.03.001
关键词
Alzheimer's disease; Neurodegeneration; Metabolic disorder; Metabolomics; Gas chromatography mass spectrometry; Brain amino-acid metabolism
资金
- Endocore Research Trust [61047]
- Maurice and Phyllis Paykel Trust [3627036]
- Lottery Health New Zealand [3626585, 3702766]
- Maurice Wilkins Centre for Molecular Biodiscovery [through a Tertiary Education Commission] [9341-3622506]
- Health Research Council of New Zealand [3338701]
- University of Auckland [JXU058]
- Oakley Mental Health Research Foundation [3456030, 3627092, 3701339, 3703253, 3702870]
- Ministry of Business, Innovation Employment [UOAX0815]
- New Zealand Neurological Foundation
- Medical Research Council [UK] [MR/L010445/1, MR/L011093/1]
- Alzheimer's Research UK [ARUK-PPG2014B-7]
- University of Manchester
- Central Manchester (NHS) Foundation Trust
- Northwest Regional Development Agency
- Alzheimers Research UK [ARUK-PPG2014B-7] Funding Source: researchfish
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. (C) 2016 The Authors. Published by Elsevier B.V.
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