Multiplatform lipid analysis of the brain of aging mice by mass spectrometry

Abstract

Lipids are an integral part of brain structure and function and represent about 50% of the dry weight of the brain. Despite their importance, the complexity and variations in the abundance of brain lipids due to aging remain poorly understood. For maximum coverage and multi-platform validation, we applied three complementary mass spectrometry-based analytical approaches: multiple reaction monitoring (MRM) profiling, untargeted liquid chromatography tandem mass spectrometry (LC-MS/MS), and desorption electrospray ionization-MS imaging (DESI-MSI). We used three different age groups of mice, namely adult (3-4 months), middle-aged (10 months) and old (19-21 months). Phospholipids including phosphatidylcholine (PC), phosphatidylethanolamine (PE) and phosphatidylglycerol (PG) showed higher abundance, while phosphatidylinositols (PI) and phosphatidylserines (PS) generally showed lower abundance in the brains of old mice compared to adults or middle-aged mice. Polyunsaturated fatty acids, such as docosahexaenoic acid (DHA) and arachidonic acid (AA), as well as hexosylceramides (HexCer), sulfated hexosylceramides (SHexCer) and sphingomyelins (SM) were among the most abundant lipid species in the brains of old mice. DESI-MSI showed variations in the spatial distribution of many of the lipids confirmed by MRM and LC-MS/MS profiling. Interrogation of lipidomic data with recent proteomics data obtained from the same tissues revealed changes in the abundance and phosphorylation levels of several proteins potentially linked to ceramide (Cer), hexosylceramide (HexCer), fatty acids (FA), phosphatidylinositol (PI), sphingomyelin (SM) and sulfatides (SHexCer) metabolism and correlated well with the multiplatform lipid surveillance. Our findings offer insight into age-dependent changes in brain lipid profiles and their potential contribution to age-related cognitive decline.