Characterization of brain‐derived extracellular vesicle lipids in Alzheimer's disease

• Published in: Journal of extracellular vesicles Vol. 10; no. 7; pp. e12089 - n/a
• Main Authors: Su, Huaqi, Rustam, Yepy H., Masters, Colin L., Makalic, Enes, McLean, Catriona A., Hill, Andrew F., Barnham, Kevin J., Reid, Gavin E., Vella, Laura J.
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.05.2021; John Wiley and Sons Inc; Wiley
• Subjects: Aged; Alzheimer Disease - metabolism; Alzheimer Disease - physiopathology; Alzheimer's disease; Biomarkers; brain; Brain - metabolism; Cancer; Central Nervous System; Cerebrospinal fluid; Cold; Cortex (frontal); Cytotoxicity; Dementia; Dementia disorders; Docosahexaenoic acid; exosomes; Exosomes - metabolism; Extracellular vesicles; Extracellular Vesicles - metabolism; Extracellular Vesicles - physiology; frontal cortex; Frontal Lobe - metabolism; glycerophospholipids; Glycerophospholipids - metabolism; Homeostasis; Humans; lipid biomarkers; Lipid composition; Lipid Metabolism - physiology; lipidome; Lipidomics - methods; Lipids; Lipids - analysis; Lymphocytes T; Male; Mass Spectrometry - methods; Mass spectroscopy; Membranes; Neurodegenerative diseases; Phosphatase; polyunsaturated fatty acids; Positron emission tomography; Proteins; Signal transduction; sphingolipids; Sphingolipids - metabolism; Sphingomyelin; tissue; Tomography, X-Ray Computed - methods; frontal cortex; extracellular vesicles; lipid biomarkers; sphingolipids; exosomes; glycerophospholipids; polyunsaturated fatty acids; tissue; lipidome; brain; Alzheimer's disease
• ISSN: 2001-3078; 2001-3078
• DOI: 10.1002/jev2.12089

Lipid dyshomeostasis is associated with the most common form of dementia, Alzheimer's disease (AD). Substantial progress has been made in identifying positron emission tomography and cerebrospinal fluid biomarkers for AD, but they have limited use as front‐line diagnostic tools. Extracellular vesicles (EVs) are released by all cells and contain a subset of their parental cell composition, including lipids. EVs are released from the brain into the periphery, providing a potential source of tissue and disease specific lipid biomarkers. However, the EV lipidome of the central nervous system is currently unknown and the potential of brain‐derived EVs (BDEVs) to inform on lipid dyshomeostasis in AD remains unclear. The aim of this study was to reveal the lipid composition of BDEVs in human frontal cortex, and to determine whether BDEVs have an altered lipid profile in AD. Using semi‐quantitative mass spectrometry, we describe the BDEV lipidome, covering four lipid categories, 17 lipid classes and 692 lipid molecules. BDEVs were enriched in glycerophosphoserine (PS) lipids, a characteristic of small EVs. Here we further report that BDEVs are enriched in ether‐containing PS lipids, a finding that further establishes ether lipids as a feature of EVs. BDEVs in the AD frontal cortex offered improved detection of dysregulated lipids in AD over global lipid profiling of this brain region.  AD BDEVs had significantly altered glycerophospholipid and sphingolipid levels, specifically increased plasmalogen glycerophosphoethanolamine and decreased polyunsaturated fatty acyl containing lipids, and altered amide‐linked acyl chain content in sphingomyelin and ceramide lipids relative to CTL. The most prominent alteration was a two‐fold decrease in lipid species containing anti‐inflammatory/pro‐resolving docosahexaenoic acid. The in‐depth lipidome analysis provided in this study highlights the advantage of EVs over more complex tissues for improved detection of dysregulated lipids that may serve as potential biomarkers in the periphery.