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. 2022 May 25;23(11):5913.
doi: 10.3390/ijms23115913.

RNA-Seq Profiling of Neutrophil-Derived Microvesicles in Alzheimer's Disease Patients Identifies a miRNA Signature That May Impact Blood-Brain Barrier Integrity

Irina Vázquez-Villaseñor  1 , Cynthia I Smith  1 , Yung J R Thang  1 , Paul R Heath  1 , Stephen B Wharton  1 , Daniel J Blackburn  1 , Victoria C Ridger  2 , Julie E Simpson  1
Affiliations

RNA-Seq Profiling of Neutrophil-Derived Microvesicles in Alzheimer's Disease Patients Identifies a miRNA Signature That May Impact Blood-Brain Barrier Integrity

Irina Vázquez-Villaseñor et al. Int J Mol Sci. .

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.

Keywords: Alzheimer’s disease; miRNA; neutrophil; neutrophil-derived microvesicles; systemic infection.

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Conflict of interest statement

The authors declare no conflict of interest. This is a summary of independent research carried out at the NIHR Sheffield Biomedical Research Centre (Translational Neuroscience). The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. Data were collected within the NIHR-funded Sheffield Clinical Research Facility.

Figures

Figure 1
Figure 1
Number of neutrophils and neutrophil microvesicles (NMV) in blood samples isolated from control and AD donors. (a) The total number of neutrophils/mL of blood was not significantly different between the two groups. (b) The total number of NMV/mL blood purified after neutrophil stimulation ex vivo did not differ significantly between control and AD donors. Mann–Whitney test (two-tailed), n = 5 per group.
Figure 1
Figure 1
Number of neutrophils and neutrophil microvesicles (NMV) in blood samples isolated from control and AD donors. (a) The total number of neutrophils/mL of blood was not significantly different between the two groups. (b) The total number of NMV/mL blood purified after neutrophil stimulation ex vivo did not differ significantly between control and AD donors. Mann–Whitney test (two-tailed), n = 5 per group.
Figure 2
Figure 2
Representative heatmap portraying the top 10 significantly dysregulated miRNAs based on the DESeq 2 (sno/miRNA track) analysis. A clear difference is seen between the AD and control groups.
See this image and copyright information in PMC

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