Vázquez-Villaseñor, I., Smith, C.I., Thang, Y.J.R. et al. (5 more authors) (2022) RNA-Seq profiling of neutrophil-derived microvesicles in Alzheimer’s disease patients identifies a miRNA signature that may impact blood–brain barrier integrity. International Journal of Molecular Sciences, 23 (11). 5913.
Abstract
(1) Background: Systemic infection is associated with increased neuroinflammation and accelerated cognitive decline in AD patients. Activated neutrophils produce neutrophil-derived microvesicles (NMV), which are internalised by human brain microvascular endothelial cells and increase their permeability in vitro, suggesting that NMV play a role in blood–brain barrier (BBB) integrity during infection. The current study investigated whether microRNA content of NMV from AD patients is significantly different compared to healthy controls and could impact cerebrovascular integrity.
(2) Methods: Neutrophils isolated from peripheral blood samples of five AD and five healthy control donors without systemic infection were stimulated to produce NMV. MicroRNAs isolated from NMV were analysed by RNA-Seq, and online bioinformatic tools were used to identify significantly differentially expressed microRNAs in the NMV. Target and pathway analyses were performed to predict the impact of the candidate microRNAs on vascular integrity.
(3) Results: There was no significant difference in either the number of neutrophils (p = 0.309) or the number of NMV (p = 0.3434) isolated from AD donors compared to control. However, 158 microRNAs were significantly dysregulated in AD NMV compared to controls, some of which were associated with BBB dysfunction, including miR-210, miR-20b-5p and miR-126-5p. Pathway analysis revealed numerous significantly affected pathways involved in regulating vascular integrity, including the TGFβ and PDGFB pathways, as well as Hippo, IL-2 and DNA damage signalling.
(4) Conclusions: NMV from AD patients contain miRNAs that may alter the integrity of the BBB and represent a novel neutrophil-mediated mechanism for BBB dysfunction in AD and the accelerated cognitive decline seen as a result of a systemic infection.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2022 The Authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
Keywords: | Alzheimer’s disease; systemic infection; neutrophil; neutrophil-derived microvesicles; miRNA |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Sheffield Teaching Hospitals |
Funding Information: | Funder Grant number Alzheimer's Research UK ARUK-PPG2018A-009 |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 01 Jun 2022 09:39 |
Last Modified: | 01 Jun 2022 09:39 |
Status: | Published |
Publisher: | MDPI AG |
Refereed: | Yes |
Identification Number: | 10.3390/ijms23115913 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:187522 |