Metabolomic-Driven Elucidation of Serum Disturbances Associated with Alzheimer';s Disease and Mild Cognitive Impairment

Abstract

Numerous efforts have been made in the last years to discover potential biomarkers of Alzheimer's disease and its progression from mild cognitive impairment, considered as an intermediate phase in the development of Alzheimer's disease from normal aging. However, there is still a considerable lack of understanding about pathological mechanisms underlying to disease. In the present study, serum metabolomics based on ultra-high-performance liquid chromatographymass spectrometry was applied to investigate metabolic differences between subjects with Alzheimer's disease and mild cognitive impairment, as well as healthy controls. The most important findings can be associated with impaired metabolism of phospholipids and sphingolipids leading to membrane breakdown, wherein the nature of the fatty acids contained in the structure in terms of acyl chain length and degree of unsaturation appears to play a crucial role. Furthermore, several discriminant metabolites were found for the first time in relation to known pathological processes associated with Alzheimer's disease, such as the accumulation of acylcarnitines in relation to mitochondrial dysfunction, decreased levels of oleamide and monoglycerides as a result of defects in endocannabinoid system, or increased serum phenylacetylglutamine, which could reveal alterations in glutamine homeostasis. Therefore, these results represent a suitable approximation to understand the pathogenesis and progression of the disease.

Lower brain and blood nutrient status in Alzheimer's disease: Results from meta‐analyses

“…The affected pathways range from fatty acid metabolism, one-carbon metabolism, energy metabolism, Krebs cycle, mitochondrial function, nucleic acid metabolism, but also neurotransmitter and amino acid metabolism, and lipid biosynthesis [165] , [166] . In line with these findings, patients with AD also show altered phospholipid metabolism [33] , [167] , [168] . As most of these metabolic pathways use nutrients, the aforementioned findings indirectly confirm the lower nutrient status observed in the current and former meta-analyses of circulatory nutrient levels.…”

Correction to: Metabolomic Fingerprinting of Blood Samples by Direct Infusion Mass Spectrometry: Application in Alzheimer’s Disease Research

“…These studies revealed significant disturbances in the homeostasis of various lipid classes (e.g., phospholipids, fatty acids, glycerolipids), energy-related metabolites, neurotransmitters, and other metabolites, thus evidencing the utility of simple and easily available serum samples in clinical research. Furthermore, these findings were then validated using orthogonal hyphenated approaches, such as UHPLC-MS [36,37], GC-MS [37,38], and CE-MS [39], demonstrating the reliability of direct MS-based metabolomics. This DIMS platform was latterly adapted for the analysis of other biological matrices, such as urine [40], brain [41], peripheral organs (i.e., liver, kidney, thymus, spleen) [42], as well as muscle, hepatopancreas, and antennal gland [43], providing very valuable results to accomplish a preliminary metabolomic screening prior to the application of other complementary techniques.…”

High-Throughput Direct Mass Spectrometry-Based Metabolomics to Characterize Metabolite Fingerprints Associated with Alzheimer’s Disease Pathogenesis

“…Alterations in serum levels of eicosanoids, amino acids and related compounds, and metabolites involved in the urea cycle demonstrated that depletion of interleukin-4 exacerbates AD pathology in this transgenic line. It should be noted that all these results obtained by DMS analysis were subsequently validated by applying various orthogonal metabolomic techniques, including LC-MS, GC-MS and CE-MS [ 45 , 46 , 47 , 48 ], thus demonstrating the potential of MS-fingerprinting approaches to carry out fast and accurate screening of complex metabolic networks.…”