Metabolomics and proteomics investigations of Alzheimer’s disease and related conditions

Abstract

Alzheimer’s disease (AD) causes the commonest form of dementia, and remains the largest unmet medical need in neurology. The cause of AD is largely unknown and to date, there are no treatments with proven disease-modifying actions. Substantial evidence has accumulated to support an important association between type-2-diabetes (T2D) and AD. Specifically, the vasculopathy aspects of T2D and AD have gained significant scientific attention, with a potential link being atherosclerosis. This study aimed to improve understanding of the molecular basis of AD pathogenesis, with focus on vascular mechanisms. Case-control studies were performed in ex-vivo rabbit aortic tissue, and postmortem brain tissue from patients. Specifically, we aimed to generate a detailed molecular profile representative of pathogenetic processes in aortic tissue from a rabbit model of atherosclerosis, and brain from AD patients. Furthermore, we aimed to measure and compare molecular changes in seven structurally and functionally distinct brain regions, to improve understanding of disease distribution in the human brain. I performed parallel proteomic analyses and metabolic profiling studies: target tissues were analysed by iTRAQ-proteomics and tissue metabolites profiled by gas-chromatography-mass-spectrometry and liquid-chromatography-mass-spectrometry. We derived a detailed description of molecular changes in human AD brain at both protein and metabolite levels, and generated quantitative protein and metabolite profiles from seven distinct brain regions. AD brain exhibited clear evidence of global perturbations in phospholipid content and defects in energy-producing mechanisms, the latter characterised by impaired glycolytic pathway and TCA cycle enzymes and metabolites, with concomitant activation of the pentose-phosphate and polyol pathways. Compared to severely affected brain regions (hippocampus and entorhinal cortex), the least affected brain region (cerebellum) exhibited molecular signatures indicative of earlier disease processes and activation of molecular defence mechanisms: these included better-preserved systems for protein folding, protein degradation, and Aβ-clearance, and lesser activation of the immune response and oxidative phosphorylation. I concluded that: accumulation of free glucose, sorbitol and fructose in AD brain is a probable cause of decreased cerebral glucose uptake as observed in patients; glycosylated proteins/lipids, interacting with relevant receptors may promote vasculopathy in atherosclerosis, T2D and AD; and, in the latter, different brain regions undergo molecular damage at different rates.