Studies on diagnostic biomarkers and therapeutic mechanism of Alzheimer's disease through metabolomics and hippocampal proteomics

Abstract

Alzheimer's disease (AD) is the main cause of dementia, but precise diagnosis and treatment are not sufficient so far. The purpose of this study is to develop biomarkers and therapeutic targets for diagnosis and better understanding of AD. As a result, lysophosphatidylcholine and intermediates of sphingolipid metabolism including sphinganine-1-phosphate, sphingosine-1-phosphate, sphingomyelin, and sphingosine in plasma were annotated as potential biomarkers by using UPLC-Q-TOF-MS and UHPLC-Q-Exactive-MS. Besides, glutathione S-transferases (GSTs) including GstA3, Gstm1, Gstm5, Gstm3, Gstk1 and Gstp1 were significantly enhanced in AD hippocampus by using label free nano-LC-MS/MS. Thus, pathogenesis of AD was involved with increasing of choline, decreasing of ACh, enhancement of GSTs and increasing of glutamate which led to oxidative stress and excitotoxity. Effects of donepezil and a natural medicine were evaluated through metabolomics and proteomics. In summary, proteomic and metabolomic analysis on constructed AD rat model were performed through rapid, sensitive and high resolution LC-MS methods to reveal candidate biomarkers. The data suggested that GSTs have great value as therapeutic targets. This study provided valuable information for the diagnosis mechanism and drug discovery of AD.

Keywords: 18:0 LYSO-PC (PubChem CID: 497299); Acetylcholine (PubChem CID: 187); Alzheimer's disease; Biomarkers; Choline (PubChem CID: 6209); Docosahexaenoic acid (PubChem CID: 445580); Glutathione S-transferases; LC-MS; Metabonomics; Proteomics; Sphinganine (PubChem CID: 91486); Sphinganine-1-phosphate (PubChem CID: 644260); Sphingolipid metabolism; Sphingomyelin (PubChem CID: 44260133); Sphingosine (PubChem CID: 5280335); Sphingosine-1-phosphate (PubChem CID: 5280903); l-glutamate (PubChem CID: 33032).