Abstract
The use of post-mortem human tissue is indispensable in studies investigating alterations in metabolite levels in neurodegenerative conditions such as Alzheimer’s disease (AD). However, variability between samples may have unknown effects on metabolite concentrations. The aim of this study was to characterize the impact of such variables. Cingulate gyrus was obtained from AD cases and controls, from three brain banks. Gas chromatography-mass spectrometry (GC-MS) was used to measure and compare the levels of 66 identifiable metabolites in these tissues to determine effects of tissue-collection variables. The effect of PMD was further investigated by analysis of rat brain cortex and cerebellum collected following post-mortem delays (PMDs) of zero to 72 h. Metabolite levels between cases and controls were not replicable across cohorts with variable age- and gender-matching, PMD, and control Braak staging. Analysis of rat tissues found significant effects of PMD on 31 of 63 identified metabolites over periods up to 72 h. PMD must be kept under 24 h for metabolomics analyses on brain tissues to yield replicable results. Tissues should also be well age- and gender-matched, and Braak stage in controls should be kept to a minimum in order to minimize the impact of these variables in influencing metabolite variability.
Highlights
Alzheimer’s disease (AD) is the most common form of age-related dementia and currently affects more than 44 million people worldwide
The cingulate gyrus was obtained from nine AD cases and nine controls from each of three geographically distinct brain banks based in Auckland, New Zealand, Manchester, and Newcastle, UK
Cingulate gyrus tissue was selected as it is a region that is widely available from brain banks and has been reported to show changes in several metabolites in AD [2]
Summary
Alzheimer’s disease (AD) is the most common form of age-related dementia and currently affects more than 44 million people worldwide. Research has aimed to determine the contributors to AD pathogenesis, including deposition of misfolded amyloid-β and tau, oxidative stress, inflammation, mitochondrial dysfunction, protein, and lipid dysregulation, such investigations have not yet led to the development of effective disease-modifying intervention [3]. Many of the identified perturbations involve metabolic processes such as purine catabolism, glucose metabolism, and amino acid pathways [4,5,6,7,8]. Such pathways may link seemingly disparate mechanisms and provide potential explanations for AD pathogenesis, and suggest new therapeutic targets
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