Abstract
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.
Highlights
Alzheimer’s disease (AD) is a neurodegenerative disorder and the most common form of dementia
These results suggest that fraction 2 (F2) contains vesicles that are consistent with the density, morphology, size and protein co-enrichment of endosome derived small brain-derived EVs (BDEVs) as we have previously reported
The most abundant lipid molecules in each lipid class are shown for clarity
Summary
Alzheimer’s disease (AD) is a neurodegenerative disorder and the most common form of dementia. Lipids are involved in maintenance of cellular homeostasis and are key components of cellular membranes They have multiple functional roles, including regulation of energy storage and signal transduction, and for the segregation of chemical reactions in discrete organelles. The homeostasis of GP has been reported to be altered in AD, with a general downregulation of glycerophosphocholine (PC), glycerophosphoethanolamine (PE) and glycerophosphoinositol (PI) species (Bennett et al, 2013; Kosicek & Hecimovic, 2013; Wong et al, 2017; Wood, 2012), with additional alterations in a specific GP subclass, namely alkenyl (i.e., plasmalogen)-containing species in AD brain (Ginsberg et al, 1995; Han et al, 2001; Pettegrew et al, 2001)
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