Metabolomic Analysis Identifies Alterations of Amino Acid Metabolome Signatures in the Postmortem Brain of Alzheimer's Disease

Abstract

Despite significant advances in neuroscience research over the past several decades, the exact cause of AD has not yet fully understood. The metabolic hypothesis as well as the amyloid and tau hypotheses have been proposed to be associated with AD pathogenesis. In order to identify metabolome signatures from the postmortem brains of sporadic AD patients and control subjects, we performed ultra performance liquid chromatography coupled with linear ion trap-Orbitrap mass spectrometer (UPLC-LTQ-Orbitrap-MS). Not only our study identified new metabolome signatures but also verified previously known metabolome profiles in the brain. Statistical modeling of the analytical data and validation of the structural assignments discovered metabolic biomarkers associated with the AD pathogenesis. Interestingly, hypotaurin, myo-inositol and oxo-proline levels were markedly elevated in AD while glutamate and N-acetyl-aspartate were decreased in the postmortem brain tissue of AD patients. In addition, neurosteroid level such as cortisol was significantly increased in AD. Together, our data indicate that impaired amino acid metabolism is associated with AD pathogenesis and the altered amino acid signatures can be useful diagnostic biomarkers of AD. Thus, modulation of amino acid metabolism may be a possible therapeutic approach to treat AD.

Targeted metabolomics study of early pathological features in hippocampus of triple transgenic Alzheimer’s disease male mice

“…Myo‐inositol is generally considered to be a marker of astroglial activity (Harris et al., 2015). Several studies have shown increased levels of this metabolite (González‐Domínguez, García‐Barrera, Vitorica, et al, 2014; Kim et al., 2019; Woo et al., 2010), except one which was consistent with our finding and was downregulated (Lalande et al., 2014). Both SAH and SMC are Hcy derivatives.…”

“…Clearly, the main pathways and related mechanisms associated with differential metabolites in 6M group are consistent with 2M group. Indeed, they have previously been reported to be associated with AD (González‐Domínguez et al., 2017; González‐Domínguez, García‐Barrera, Vitorica,, et al., 2014; Griffin & Bradshaw, 2017; Kim et al., 2019; Kori et al., 2016; Toledo et al., 2017; Varma et al., 2018). However, the 6M group produced more differential metabolites than the 2M group.…”

“…group. Indeed, they have previously been reported to be associated with AD (González-Domínguez et al, 2017;González-Domínguez, García-Barrera, Vitorica,, et al, 2014;Griffin & Bradshaw, 2017;Kim et al, 2019;Kori et al, 2016;Toledo et al, 2017;Varma et al, 2018).…”

Mechanistic Insights into Alzheimer’s Disease Unveiled through the Investigation of Disturbances in Central Metabolites and Metabolic Pathways

“…A similar analytical approach was employed to predict the progression of AD along four diagnostic groups, namely healthy control subjects, stable MCI patients, MCI subjects who developed AD after a 2-year follow-up, and AD patients, which indicated significant alterations in the CSF levels of some amino acids and taurine-related metabolites [ 52 ]. Comparable findings have been obtained from brain metabolomics profiling, thus suggesting that modulating the metabolism of amino acids could be a possible therapeutic approach against AD [ 53 ]. Additionally, in the brain, Paglia et al found profound cortical perturbations in the metabolism of glycerophospholipids and six central metabolic pathways, of which a significant impairment of the mitochondrial aspartate metabolism was noteworthy [ 54 ].…”

Stop the rot. Enzyme inactivation at brain harvest prevents artifacts

“…D-Glutamate (Glu) is not present in brain although it is present in blood (Weatherly et al, 2017) and inclusion of the D-glutamine (Gln) and D-Glu metabolism pathway in brain is not correct. (Kim et al, 2019).…”