Characterising Alzheimer's disease through integrative NMR- and LC-MS-based metabolomics

Abstract

Background Alzheimer's Disease (AD) is a complex and multifactorial disease and novel approaches are needed to illuminate the underlying pathology. Metabolites comprise the end-product of genes, transcripts, and protein regulations and might reflect disease pathogenesis. Blood is a common biofluid used in metabolomics; however, since extracellular vesicles (EVs) hold cell-specific biological material and can cross the blood-brain barrier, their utilization as biological material warrants further investigation. We aimed to investigate blood- and EV-derived metabolites to add insigts to the pathological mechanisms of AD. Methods Blood samples were collected from 10 AD and 10 Mild Cognitive Impairment (MCI) patients, and 10 healthy controls. EVs were enriched from plasma using 100,000× g , 1 h, 4 °C with a wash. Metabolites from serum and EVs were measured using liquid chromatography-mass spectrometry (LC-MS) and nuclear magnetic resonance (NMR) spectroscopy. Multivariate and univariate analyses were employed to identify altered metabolites in cognitively impaired individuals. Results While no significant EV-derived metabolites were found differentiating patients from healthy individuals, six serum metabolites were found important; valine ( p = 0.001, fold change, FC = 0.8), histidine ( p = 0.001, FC = 0.9), allopurinol riboside ( p = 0.002, FC = 0.2), inosine ( p = 0.002, FC = 0.3), 4-pyridoxic acid ( p = 0.006, FC = 1.6), and guanosine ( p = 0.004, FC = 0.3). Pathway analysis revealed branched-chain amino acids, purine and histidine metabolisms to be downregulated, and vitamin B6 metabolism upregulated in patients compared to controls. Conclusion Using a combination of LC-MS and NMR methodologies we identified several altered mechanisms possibly related to AD pathology. EVs require additional optimization prior to their possible utilization as a biological material for AD-related metabolomics studies.

Metabolic Features of Brain Function with Relevance to Clinical Features of Alzheimer and Parkinson Diseases

“…The decreased levels of BCAAs could affect glutamate synthesis, thereby impairing neurotransmission. Indeed, in line with lower BCAA levels in AD, a reduction in glutamate levels was reported in AD patients [ 266 ], together with decreased levels of glutamine [ 267 ]. Furthermore, since glutamate, as an excitatory neurotransmitter, binds to cell surface receptors such as α-amino-3-hydroxy-5-methyl-4-isoxazolopropionic acid (AMPA) receptors and N-methyl-D-aspartate (NMDA) receptors [ 268 ], and since reduction in NMDA receptor function relates to Ca 2+ dysregulation and reduced synaptic plasticity [ 269 ], it is conceivable that reduced BCAA levels contribute to dementia in AD [ 265 ] ( Figure 3 B).…”

A multi‐omics analysis for the prediction of neurocognitive disorders risk among the elderly in Macao

“… 40 4‐Pyridoxic acid is the product of vitamin B 6 , and it was increased in serum of MCI (mild cognitive impairment) and AD patients. 41 The main function of pantothenic acid, also called vitamin B 5 , is the synthesis of CoA and acyl carrier protein. A study had found that dietary intake of pantothenic acid was associated with cerebral amyloid burden in patients with cognitive impairment.…”

“…Moreover, a cross‐sectional study in the older hospitalized patients revealed that patients with dementia and delirium had lower whole blood thiamine compared to those without 40 . 4‐Pyridoxic acid is the product of vitamin B 6 , and it was increased in serum of MCI (mild cognitive impairment) and AD patients 41 . The main function of pantothenic acid, also called vitamin B 5 , is the synthesis of CoA and acyl carrier protein.…”

“…40 4-Pyridoxic acid is the product of vitamin B 6 , and it was increased in serum of MCI (mild cognitive impairment) and AD patients. 41 The main function of pantothenic acid, also called vitamin B 5 , is the synthesis of CoA and acyl carrier protein.…”

Inosine in Neurodegenerative Diseases: From the Bench to the Bedside

“…Of note, Nielsen et al found that inosine serum levels were reduced in AD patients [ 29 ]. Moreover, Alonso-Andrés et al demonstrated that the frontal cortex from the early stages of AD show apparently reduced levels of inosine, whereas the parietal cortex and temporal cortex show significantly higher levels of inosine, at least at certain stages of AD [ 30 ].…”