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

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journal contribution
posted on 28.06.2021, 03:46 by Huaqi Su, Yepy H Rustam, Colin L Masters, Enes Makalic, Catriona A McLean, Andrew Hill, Kevin J Barnham, Gavin E Reid, Laura J Vella
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.

Funding

Australian National Health and Medical Research Council, Grant/Award Numbers: GNT1041413, GNT1002349, 628946; Australian Research Council, Grant/Award Number: LE160100015; Bethlehem Griffiths Research Foundation; Alzheimer's Australia Dementia Research Foundation John Shutes Project Grant; Alzheimer's Association, Grant/Award Number: AARF-18-566256

History

Publication Date

11/05/2021

Journal

Journal of Extracellular Vesicles

Volume

10

Issue

7

Article Number

e12089

Pagination

14p.

Publisher

Wiley

ISSN

2001-3078

Rights Statement

The Author reserves all moral rights over the deposited text and must be credited if any re-use occurs. Documents deposited in OPAL are the Open Access versions of outputs published elsewhere. Changes resulting from the publishing process may therefore not be reflected in this document. The final published version may be obtained via the publisher’s DOI. Please note that additional copyright and access restrictions may apply to the published version.