Brain lipidomics: From functional landscape to clinical significance

Abstract

Lipids are crucial components of cellular function owing to their role in membrane formation, intercellular signaling, energy storage, and homeostasis maintenance. In the brain, lipid dysregulations have been associated with the etiology and progression of neurodegeneration and other neurological pathologies. Hence, brain lipids are emerging as important potential targets for the early diagnosis and prognosis of neurological diseases. This review aims to highlight the significance and usefulness of lipidomics in diagnosing and treating brain diseases. We explored lipid alterations associated with brain diseases, paying attention to organ-specific characteristics and the functions of brain lipids. As the recent advances in brain lipidomics would have been impossible without advances in analytical techniques, we provide up-to-date information on mass spectrometric approaches and integrative analysis with other omic approaches. Last, we present the potential applications of lipidomics combined with artificial intelligence techniques and interdisciplinary collaborative research for treating brain diseases with clinical heterogeneities.

Fig. 1.. Functions and characteristics of brain lipids.

Brain lipids are primarily composed of PC, cholesterol (Chol), PE, phosphatidylserine (PS), and SM, which are involved in brain functions including organ homeostasis, cell formation and maintenance, and signal transduction. Chol is synthesized in astrocytes and transferred to neurons via the formation and secretion of Chol-rich apolipoprotein (APOE-Chol). Certain Chols of neurons are transformed into 24-hydroxycholesterols (24-OHCs), which are then released into bloodstream. The degradation of glycerophospholipids by phospholipase A (PLA), phospholipase C (PLC), and phospholipase D (PLD) leads to the generation of second messengers. Neurodevelopment progresses via the regulation of enzymes associated with lipid synthesis, such as ceramide synthase 2 (CerS2), ceramide galactosyltransferase (CST), ceramide galactosyltransferase (CGT), and N-acetyl-α-neuraminidase 3 (Neu3). PIP, phosphatidylinositol-phosphate; GSL, glycosphingolipid; GluCer, glucosylceramide; FFA, free fatty acid.

Fig. 2.. MS-based analytical strategy for brain lipidomics research.

Lipidomic analysis of brain tissues and biofluids involves sample treatment, MS analysis, and data processing. The general strategy of lipidomics involves lipid extraction followed by the separation and detection of lipid mixtures using LC-MS (right arrow). Conversely, lipid imaging using MALDI-MSI involves the direct analysis of lipids in brain tissue slices without their extraction. Here, the frozen brain tissue is sectioned and matrix-coated before MS analysis. Following analysis, the MS data of lipids, such as mass value and ion intensity, are converted into an image file (left arrow). m/z, mass-to-charge ratio. HRMS, high-resolution mass spectrometry; PRM, parallel reaction monitoring; MTBE, methyl-tert-butyl ether.

Fig. 3.. Future direction for brain research using multi-omics.

The advancement of brain research requires interdisciplinary collaborative research encompassing fields such as basic science, technology, and clinical research, to systematically understand brain functions and medical applications. As a starting point, the analysis of human brain specimens using multi-omics coupled with AI technology will provide critical information necessary to untangle the molecular networks in the brain. Lipidomics serves as the main component of brain omics.