• Lipids account for over 50% of human brain dry weight
• A cell-type-resolved molecular assessment of neural cells
• Lipidomics revealed specific lipid profiles for neurons and glia cell types
ABOUT 75% of all mammalian lipid species are exclusively found in neural tissues. In their variety, lipids contribute to the morphological and functional diversity of the central nervous system consisting of neurons and glia cells.
As a key component of neural cells, lipids hold significant information in the efforts to better understand the human brain, its diseases and mental disorders. Thus, detailed, molecular lipid analysis is an adequate tool for cell-type-resolved assessments of lipid composition and lipid metabolism.
The central nervous system and the peripheral nervous system consist of electrically excitable cells, neurons, and cells that do not produce electrical impulses but provide vital support, glia cells. Glia cells in the central nervous system include oligodendrocytes, astrocytes, and microglia. The primary function of oligodendrocytes is to generate myelin, a multilamellar membrane stack that insulates the axons of neurons. Astrocytes recycle neurotransmitters, shape synaptic circuits, and maintain the blood-brain barrier. Microglia are mainly related to immune responses and brain homeostasis, and play a crucial role in myelination and remyelination.
During evolution the increasing complexity of the mammalian central nervous system was accompanied by an ever growing specialization of its lipid species. Indeed, lipids and lipid metabolism play an enormously important role in the structure and function of brain tissue, and thus brain health.
The molecular composition of the human brain: Average distribution of major classes of molecules in the human brain. Lipids account for more than 50% of human brain dry weight. H McIlwain & H S Bachelard, Churchill Livingstone (1985), ISBN: 0-443-01961-4
Certain lipid classes and even distinct lipid species are known to be enriched in specific cell types. For example, neurons and myelin contain high levels of cholesterol. Galactosylceramides, which belong to the hexosylceramides, are typically accumulating exclusively in the membrane of oligodendrocytes during myelination. Specific lipids are required for specific neural cells and their functions. Yet, many of these links remain to be discovered and understood.
The mouse brain serves as a powerful animal model to study the human brain, its diseases, and mental disorders. The genes responsible for building and operating both mouse and human brain are highly concordant.
Human and mouse brain: The cellular architecture of the human and mouse brain tissues are well-conserved. They are organized in very similar fashion and contain a comparable diversity of cell types.
Researchers from the German Center for Neurodegenerative Diseases aimed to generate a cell-type-resolved lipidomic profile of the mouse brain – in order to acquire a basic yet distinctive dataset for further neurobiological research. They applied lipidomics analysis to differentiate the lipid composition of neurons and different glia cell types, including astrocytes, oligodendrocytes, and microglia.
Overall, 23 lipid classes were analyzed, and about 750 individual lipids identified and quantified. Of these, 13 lipid classes comprised more than 99% of all quantified lipids. Phosphatidylcholine and cholesterol were the two most common lipid classes in all four sample types. However, when comparing the different cell types, profound differences in the lipidomic profiles ranging from lipid classes to lipid species were discovered.
Lipid class distribution in mouse central nervous system cells: Average distribution of the 13 most abundant lipid classes in primary cell cultures of neurons, oligodendrocytes, microglia, and astrocytes. D Fitzner et al., Cell Reports (2020), doi: 10.1016/j.celrep.2020.108132
Elevated levels of lipid classes like phosphatidylcholine, phosphatidylethanolamine, and cholesterol were found in neurons. Though otherwise not rich in phosphatidylglycerols, lipid species data showed they were also enriched in selected phosphatidylglycerol lipids.
Oligodendrocytes were the most diverging cell type, most likely because of their role in producing myelin, with its unique lipid composition. Indeed, sulfatide and hexosylceramide were enriched in oligodendrocytes, two lipid classes comprising structural lipids of myelin.
Interestingly, microglia were rich in phosphatidylglycerols and sphingomyelins, containing high levels of specific sphingomyelin lipids which are almost absent from neurons and oligodendrocytes.
Astrocytes contained higher levels of two types of phospholipids, phosphatidylserine and phosphatidylinositol, and diacylglycerols. Though otherwise not enriched in phosphatidylethanolamines, they were also particularly rich in two specific phosphatidylethanolamine lipid species.
Lipid class composition of mouse central nervous system cell types: Average distribution of the 20 most abundant lipid classes in primary cell cultures of neurons, oligodendrocytes, microglia, and astrocytes. D Fitzner et al., Cell Reports (2020), doi: 10.1016/j.celrep.2020.108132
Each neural cell type features a distinct lipid composition, thus expanding the research project to the question whether each cell type adapts specific lipid metabolism pathways too. In a multiomics approach, the new lipid profiles of neurons and glia cells were linked to previously acquired proteomics data, and distinct lipid metabolism profiles for each cell type were revealed.
Pathways related to arachidonic acid, a fatty acid deeply involved in inflammation signaling, were enriched in microglia, a type of glia cells which are mainly related to immune responses and brain homeostasis. On the other hand, an expected increase in pathways related to cholesterol and hexosylceramide biosynthesis for the production of myelin were found in oligodendrocytes. Upregulated pathways in neurons revolved mainly around phospholipid and cholesterol biosynthesis, and those enriched in astrocytes involved types of β-oxidation for the breakdown of lipids.
Better understanding of the brain and its functions will help improve treatment of neurodegenerative diseases such as multiple sclerosis, Alzheimer’s, Parkinson’s, but also epilepsy and even migraines.
Lipotype Lipidomics technology provides academic, industry and clinical researchers from neurobiology the means to perform comprehensive analyses of lipids in neurons and glia cells for detailed insight into the brain.
The DZNE explores brain diseases. Their research is closely linked to clinical research, population studies, health care research and systems medicine, to identify new diagnostic markers and to enable rapid development of new therapies.
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