Unraveling metabolic alterations in transgenic mouse model of Alzheimer's disease using MALDI MS imaging with 4-aminocinnoline-3-carboxamide matrix

Revealing the metabolic abnormalities of central and peripheral systems in Alzheimer's disease (AD) mouse model is of paramount importance for understanding AD disease. Matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI) is a powerful label-free technique that has been extensively utilized for the interrogation of spatial changes of various metabolites in neurodegenerative disease. However, technical limitations still exist in MALDI MS, and there is a need to improve the performance of traditional MALDI for a deeper investigation of metabolic alterations in the AD mouse model. In this work, 4-aminocinnoline-3-carboxamide (4-AC) was developed into a novel dual-polarity MALDI matrix. Compared with traditionally used MALDI matrices such as 2,5-dihydroxybenzoic acid (DHB) and 9-aminoacridine (9-AA), 4-AC exhibited superior performance in UV absorption at 355 nm, ion yields, background interference, and vacuum stability, making it an ideal MALDI matrix for comprehensive evaluation of metabolic alteration in the brain and serum of APP/PS1 transgenic mouse model of AD. In total, 93 metabolites exhibited different levels of regional changes in the brain of AD mice as compared to the age-matched controls. Moreover, in the serum of AD mice, 81 altered metabolites distinguishing the AD group from the control were observed by using multivariate statistical analysis. It is expected that the application of the MALDI MSI method developed in this work to visualize the spatio-chemical change of various metabolites may improve our understanding of the etiopathogenesis of AD.