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Updated: May 8, 2026

Harnessing the Power of MicroRNA Cargoes in Small Extracellular Vesicles Released from Fresh-Frozen Human Brain Sections
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Neuron-Enriched Extracellular Vesicle MicroRNAs Reflect Hormone-Sensitive Neural Pathway Changes from Early to Late

Rebekah L Frye1, Dana M Lapato2, Christopher Sikes-Keilp3

  • 1University of Virginia, School of Medicine, Neuroscience Graduate Program, Charlottesville, VA.

Medrxiv : the Preprint Server for Health Sciences
|May 7, 2026
PubMed
Summary

During perimenopause, neuron-enriched extracellular vesicle (nEV) microRNA (miRNA) profiles shift. Late perimenopause shows coordinated changes in nEV miRNA expression, potentially reflecting altered neuronal regulation.

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Area of Science:

  • Neuroendocrinology
  • Molecular Neuroscience
  • Biomarker Discovery

Background:

  • The menopausal transition involves significant neuroendocrine changes, impacting cognitive and affective functions.
  • Few in vivo biomarkers directly reflect hormone-sensitive neural adaptations.
  • Neuron-enriched extracellular vesicles (nEVs) in blood offer a minimally invasive method to study central nervous system (CNS) biology via carried microRNAs (miRNAs).

Purpose of the Study:

  • To investigate differences in L1 cell adhesion molecule (L1CAM)-positive nEV miRNA profiles between early and late perimenopause.
  • To identify potential blood-based biomarkers for neuroendocrine shifts during the menopausal transition.

Main Methods:

  • Pilot study comparing nEV miRNA profiles in early (STRAW -2) and late (STRAW -1) perimenopausal women.
  • Discovery screen of 179 miRNAs followed by individual quantification using qPCR.
  • Bioinformatic analysis of predicted mRNA targets and pathway enrichment.

Main Results:

  • A significant main effect of STRAW stage was observed, with late perimenopause associated with lower overall expression of the measured miRNA panel.
  • Coordinated shifts in miRNA expression were noted, not miRNA-specific regulation.
  • No association found between nEV miRNA expression and estradiol levels or symptom severity.
  • Bioinformatic analysis revealed enrichment of the gonadotropin-releasing hormone (GnRH) receptor pathway and related signaling pathways.

Conclusions:

  • nEV miRNA profiles exhibit stage-related differences during the menopausal transition.
  • These findings suggest altered hormone-sensitive neuronal regulatory processes during perimenopause.
  • L1CAM-positive nEVs may serve as a valuable tool for monitoring CNS changes during reproductive aging.