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.
Highlights
Alzheimer’s disease (AD) is the most common cause of adultonset dementia
We used an innovative analytical approach based on a combination of untargeted and targeted lipidomic and metabolomics, as well as mass spectrometry (MS) imaging, to investigate metabolic alterations occurring in the AD brain
We explored the biochemical significance of observed metabolic alterations according to known metabolic pathways
Summary
Alzheimer’s disease (AD) is the most common cause of adultonset dementia. Rising life expectancy is associated with increased prevalence and incidence of dementia. A recent report estimates that one in every three people born in the United Kingdom in 2015 will suffer from this debilitating mental illness during their lifetime.[1] The need to identify novel molecular targets for AD to use in diagnostics and therapeutics is acute. A growing number of clinical research laboratories use mass spectrometry (MS) applications to investigate proteomic changes in AD,[2−6] insufficient effort has been dedicated to studying alterations in levels of small molecules, metabolites, and lipids.[2,7−9] To effectively address any therapeutic challenge in AD, requires detailed information about its underlying molecular pathology. Changes in selected lipids or metabolites in AD brains, it is speculated, result from a cascade of cellular events involving abnormal β-amyloid protein metabolism, τ
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