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MicroRNA expression within neuronal-derived small extracellular vesicles in frontotemporal degeneration

Pounders, Jonathan, Hill, Emily J., Hooper, Destiny, Zhang, Xiang, Biesiada, Jacek, Kuhnell, Damaris, Greenland, Hannah L., Esfandiari, Leyla, Timmerman, Emerlee, Foster, Forrest, Wang, Chenran, Walsh, Kyle B., Shatz, Rhonna, Woo, Daniel, Medvedovic, Mario, Langevin, Scott, Sawyer, Russell P.·2022·Medicine
DOI 10.1097/md.0000000000030854PMC PMC9542922
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Abstract

MicroRNAs (miRNAs) are small non-coding RNA that are powerful regulators of gene expression and can affect the expression of hundreds of genes. miRNAs can be packed in small extracellular vesicles (SEV) and released into the extracellular space by neurons and microglia to act locally as well as pass through the blood-brain barrier and act systemically. We sought to understand the differences in neuronal SEV miRNA expression between frontotemporal dementia (FTD), Alzheimer’s disease (AD), and healthy aging. Plasma was obtained from FTD, AD, and healthy aging participants that were matched based on age, sex, and race/ethnicity. Additionally, a subset of participants also provided paired cerebrospinal fluid samples to compare neuronal SEV miRNAs in plasma and cerebrospinal fluid. Neuronal SEV were isolated using differential ultracentrifugation and antibody conjugated Dynabeads® for the neuronal surface marker, L1CAM. RNA sequencing was performed. 12 FTD, 11 with AD, and 10 healthy aging participants were enrolled in the study. In FTD, SEV miRNA-181c was downregulated compared to healthy controls. In AD, miRNA-122 and miRNA-3591 were downregulated compared to those in healthy controls and FTD. Using an FDR <0.2, only miRNA-21-5p was found to have increased expression in the cerebrospinal fluid compared to plasma in a group of AD and FTD participants. SEV miRNA-181c is significantly downregulated in FTD compared to healthy controls and may mediate its effects through microglial-directed neuroinflammation and interaction with TAR DNA-binding protein 43 (TDP-43) based on pathway analysis. Additionally, the FOXO and Hippo pathways may be important mediators of FTD, based on pathway analysis. Lastly, because only one SEV miRNA was differentially expressed between the plasma and cerebrospinal fluid in paired samples, plasma represents an appropriate biofluid for studying neuronal SEV miRNA.

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Metadata

Authors
Pounders, J., Hill, E. J., Hooper, D., Zhang, X., Biesiada, J., Kuhnell, D., Greenland, H. L., Esfandiari, L., Timmerman, E., Foster, F., Wang, C., Walsh, K. B., Shatz, R., Woo, D., Medvedovic, M., Langevin, S., & Sawyer, R. P.
Affiliations
  • University of Cincinnati College of Medicine, Department of Neurology and Rehabilitation Medicine, Cincinnati, OH, USA
  • University of Cincinnati College of Medicine, Department of Environmental and Public Health Sciences, Cincinnati, OH, USA
  • University of Cincinnati, Department of Electrical Engineering and Computer Science, Cincinnati, OH, USA
  • University of Cincinnati College of Medicine, Department of Cancer Biology, Cincinnati, OH, USA
  • University of Cincinnati College of Medicine, Department of Emergency Medicine, Cincinnati, OH, USA.
ORCID
Sawyer, Russell P.
Venue
Medicine
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2022-10-07
Volume
101
Issue
40
Pages
e30854
ISSN
1536-5964
DOI
10.1097/md.0000000000030854
PMC
PMC9542922
Cited by
26
References
2
Language
en
Licence
creativecommons.org/licenses/by/4.0/ (unspecified)

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