Metabolomic screening of regional brain alterations in the APP/PS1 transgenic model of Alzheimer's disease by direct infusion mass spectrometry

Abstract

The identification of pathological mechanisms underlying to Alzheimer's disease is of great importance for the discovery of potential markers for diagnosis and disease monitoring. In this study, we investigated regional metabolic alterations in brain from the APP/PS1 mice, a transgenic model that reproduces well some of the neuropathological and cognitive deficits observed in human Alzheimer's disease. For this purpose, hippocampus, cortex, cerebellum and olfactory bulbs were analyzed using a high-throughput metabolomic approach based on direct infusion mass spectrometry. Metabolic fingerprints showed significant differences between transgenic and wild-type mice in all brain tissues, being hippocampus and cortex the most affected regions. Alterations in numerous metabolites were detected including phospholipids, fatty acids, purine and pyrimidine metabolites, acylcarnitines, sterols and amino acids, among others. Furthermore, metabolic pathway analysis revealed important alterations in homeostasis of lipids, energy management, and metabolism of amino acids and nucleotides. Therefore, these findings demonstrate the potential of metabolomic screening and the use of transgenic models for understanding pathogenesis of Alzheimer's disease.

Small molecule biomarkers in Alzheimer’s disease

“…The findings demonstrated significant impairments in energy metabolism, lipid homeostasis, oxidative stress and amino acids metabolism. These findings were largely consistent with those found from Tg mouse brain tissue samples (Lin et al, 2014;Lin et al, 2013;Gonzalez-Dominguez et al, 2015h). These findings highlighted the systemic nature of AD as metabolite dysregulation was seen in multi-organs, not just the brain.…”

“…Direct MS analysis on APP transgenic mouse cortex and cerebellum showed lower sulfatide levels (Cheng et al, 2010), while perturbations in homeostasis of lipids, energy management, and metabolism of amino acids and nucleotides were visible on APPxPS1 hippocampus and cortex (Gonzalez-Dominguez et al, 2015h). Employing ultra high resolution MS instruments, Lin et al, (2013) were able to observe over-production of eicosanoids indicating neuroinflammation on hippocampal tissues (Lin et al, 2013), and enhanced biosynthesis of amino acid and amino acid derivatives in cerebellum (Lin et al, 2014).…”

Metabolomic research on the role of interleukin-4 in Alzheimer’s disease

“…1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 Numerous efforts have been made in the last years to identify metabolic failures associated with pathological mechanisms underlying to Alzheimer's disease. To this end, different authors have previously addressed the metabolomic investigation of several mouse models of AD using both brain tissue and blood samples, such as theG APP/PS1 E9 (González-Domínguez et al 2014b;2015a), TASTPM (Hu et al, 2012;, CRND8 (Salek et al, 2010;Lin et al, 2013;Lin et al, 2014), APP/PS1 M146L (Woo et al, 2010;Trushina et al, 2012), APP Tg2576 Lalande et al, 2014) or SAMP8 (Jiang et al, 2008;Wang et al, 2014), among others. Thereby, multiple associations have been described between Alzheimer's disease and metabolic perturbations such as oxidative stress, mitochondrial dysfunction, abnormal lipid metabolism or inflammatory processes.…”

Metabolomic Fingerprinting of Blood Samples by Direct Infusion Mass Spectrometry: Application in Alzheimer’s Disease 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. Lin et al also described the application of DIMS-based metabolomics to investigate the characteristic neurochemical profile of the CRND8 transgenic mice.…”