Brain Lipidomics: From Function to Disease (Part 1)

We are very pleased to share a review published in Science Advances. The authors of ”Brain lipidomics: From functional landscape to clinical significance (doi: 10.1126/sciadv.adc9317)” aims to highlight the significance and usefulness of lipidomics in diagnosing and treating brain diseases, and explore lipid alterations associated with brain diseases, paying attention to organ-specific characteristics and the functions of brain lipids. 


Brain diseases such as neurodegenerative diseases, psychiatric diseases, and brain tumors are being increasingly recognized as major causes of morbidity and death. Particularly, most neurodegenerative diseases are still diagnosed based on clinical symptoms, such as cognitive decline, motor disturbances, and communication difficulties, and their underlying pathological mechanisms remain unclear, thus limiting the number of treatment approaches available.


Lipids are essential components of cellular functions, as they play roles in cell membrane formation, intercellular signaling, energy storage, and maintaining internal homeostasis. In the brain, lipid dysregulation is associated with the etiology and progression of neurodegenerative and other neurological diseases. Brain lipidomics is becoming an important potential target for early diagnosis and prognosis of neurological diseases. 


The main components and functions of brain lipids


Lipids act as key constituents of cell membranes. Among all organs and tissues in the human body, the brain has the second-highest lipid content after adipose tissues, accounting for 50% of its dry weight. Brain lipids mainly consist of cholesterol (30%), glycerophospholipids (49%, of which 33% is phosphatidylcholine and 16% is phosphatidylethanolamine), and 6% sphingolipids (as shown on the left figure).


Free fatty acids are an important source for the synthesis of glycerophospholipids and sphingolipids. Furthermore, unsaturated fatty acids like docosahexaenoic acid (DHA) and arachidonic acid modulate synaptic plasticity and neuronal transmission. While its ability to synthesize polyunsaturated FAs (PUFAs) is relatively poor, the brain primarily produces saturated fatty acids (FAs) and obtain unsaturated fatty acids from peripheral blood. (Click here to see classification of fatty acids)


The cerebrospinal fluid typically contains primary metabolites diffused from the brain, making it a unique sample source that reflects brain disease pathology. Lipids in cerebrospinal fluid and blood have been considered potential biomarkers in patients with Alzheimer's disease (AD), Parkinson's disease (PD), and schizophrenia (SCZ).


01 Cholesterol


Brain cholesterol accounts for 25% of the total body cholesterol. It is primarily produced by astrocytes and transferred to neurons through cholesterol-rich lipoproteins (such as apolipoprotein E, APOE), maintaining neurite and synaptic connections.


Endogenous cholesterol in the brain is mainly found in myelin sheaths. Compared to other tissues, the brain has higher levels of non-esterified cholesterol. About 1% of brain cholesterol is esterified and appears in the form of lipid droplets, storing excess cholesterol within cells.


Most steroids in the central nervous system (CNS) are synthesized in situ (except for a few exceptions like blood-free cholesterol, mainly 24-hydroxycholesterol, which can penetrate the blood-brain barrier into the CNS). The blood-brain barrier largely hinders the exchange of steroids between the CNS and peripheral tissues, resulting in a daily exchange rate between the brain and periphery less than 1%. Thus, cholesterol metabolism in the brain can be considered largely independent of peripheral tissues, making normal cholesterol homeostasis crucial for maintaining brain function, and its disruption can lead to neurodegenerative diseases and cognitive impairment in the elderly  (as shown on the figure above ).


02 Glycerophospholipid

Glycerophospholipids, including PC and PE, are the major phospholipid components of cell membranes. Alterations in their composition can influence the stability, permeability, and fluidity of neuronal membranes, leading to neurological diseases. Similar to other tissues, PC and PE in brain cells usually control the membrane anchoring of proteins. Additionally, phospholipases A, C, and D, through receptor-mediated degradation of glycerophospholipids, lead to the generation of second messengers such as diacylglycerol (DAG), inositol 1,4,5-trisphosphate, lysophosphatidylcholine, platelet-activating factor, and long-chain polyunsaturated fatty acids (LCPUFAs). Particularly, LCPUFAs serve as precursors for omega-6 and omega-3 fatty acids, which play critical neuroprotective and anti-inflammatory roles in the central nervous system.


03 Sphingolipid


Sphingolipids, commonly found in the nervous system, are important constituents of cell membranes, primarily categorized into three classes: sphingophospholipids, cerebrosides, and gangliosides. They participate in neurogenesis and synaptogenesis, maintaining brain function. Sphingolipids and cholesterol in lipid rafts are associated with the activity of transmembrane proteins, while sphingolipids in synaptic membranes interact with neurotransmitter receptors and regulate their activity.


Sphingolipids comprise sphingomyelin (SM), gangliosides, cerebrosides, and sulfatides, all of which are derived from ceramides (N-acylsphingosine). SM, as a major component of myelin sheaths, has a higher content in the brain's white matter. Cerebrosides also have a higher content in white matter compared to gray matter. Most of the cerebrosides in the brain are lactosylceramides. Glycosynapses consist of lactosylceramides and sulfatides, playing a role in the long-term stability of myelin sheaths. Gangliosides are a class of glycosphingolipids with sialic acid residues, and they are abundant in the central nervous system, being associated with cell signaling and neuroprotection. During neural stem cell proliferation, the ganglioside GD3 in cell microdomains initially co-localizes with the epidermal growth factor receptor, and then, by inhibiting the degradation of glycosphingolipids and overexpressing N-acetylneuraminidase 3 (Neu3), it stimulates axonal growth of neuroblastoma cells (as shown on the figure above ).


04 MS-based lipidomics

Several techniques have been employed for brain lipidomics research, including nuclear magnetic resonance (NMR) spectroscopy, fluorescence analysis, and mass spectrometry, each demonstrating different analytical performance in terms of sensitivity and efficiency. Fluorescence analysis is the simplest technique for quantifying specific lipid components but is not suitable for in-depth lipid analysis. Compared to mass spectrometry, NMR has non-destructive sample preparation and detailed structural elucidation capabilities but lower sensitivity. Advanced mass spectrometry, on the other hand, offers high sensitivity and high resolution, enabling in-depth analysis of a large number of lipids, including isomers.


MS-based-analytical-strategy-for-brain-lipidomics-research.pngThe diagram on the left illustrates a simplified workflow for mass spectrometry-based brain lipidomics research. Brain tissue and biological fluids, such as serum, plasma, and cerebrospinal fluid, are extracted using liquid-liquid extraction methods like Folch, Bligh, and Dyer, and methyl tert-butyl ether or butanol/methanol. Both untargeted and targeted approaches can be used for brain lipid analysis. However, for the detection of lipid molecules relevant to brain diseases or the exploration of potential biomarkers, targeted quantification based on triple quadrupole (QQQ) mass spectrometry with multiple reaction monitoring (MRM) is commonly employed, which provides significant advantages in targeted quantification of key lipid molecules.


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