Mass spectrometry imaging shows major derangements in neurogranin and in purine metabolism in the triple-knockout 3×Tg Alzheimer mouse model.

ABSTRACT

Matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging (MSI) can simultaneously measure hundreds of biomolecules directly from tissue. Using different sample preparation strategies, proteins and metabolites have been profiled to study the molecular changes in a 3×Tg mouse model of Alzheimer's disease. In comparison with wild-type (WT) control mice MALDI-MSI revealed Alzheimer's disease-specific protein profiles, highlighting dramatic reductions of a protein with m/z 7560, which was assigned to neurogranin and validated by immunohistochemistry. The analysis also revealed substantial metabolite changes, especially in metabolites related to the purine metabolic pathway, with a shift towards an increase in hypoxanthine/xanthine/uric acid in the 3×Tg AD mice accompanied by a decrease in AMP and adenine. Interestingly these changes were also associated with a decrease in ascorbic acid, consistent with oxidative stress. Furthermore, the metabolite N-arachidonyl taurine was increased in the diseased mouse brain sections, being highly abundant in the hippocampus. Overall, we describe an interesting shift towards pro-inflammatory molecules (uric acid) in the purinergic pathway associated with a decrease in anti-oxidant level (ascorbic acid). Together, these observations fit well with the increased oxidative stress and neuroinflammation commonly observed in AD. This article is part of a Special Issue entitled MALDI Imaging, edited by Dr. Corinna Henkel and Prof. Peter Hoffmann.