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Updated: Sep 13, 2025
Harnessing the Power of MicroRNA Cargoes in Small Extracellular Vesicles Released from Fresh-Frozen Human Brain Sections
Published on: November 8, 2024
The intersection between circulatory microRNAs and biomarkers of neurodegeneration
Amber Yaqub1, Rima Mustafa2, M Arfan Ikram1
1Department of Epidemiology, Erasmus University Medical Center, Dr. Molewaterplein 40, Rotterdam, 3015 GD, the Netherlands.
Background:
MicroRNAs (miRNAs) are small non-coding RNAs with a vast array of biological functions, including the regulation of gene expression. It remains to be determined whether circulatory miRNAs are associated with markers of neurodegeneration in plasma (neurofilament light chain (NfL), total tau (t-tau) and amyloid beta (Aβ)), before the clinical onset of dementia.
Methods:
We included 1959 dementia-free participants of the population-based Rotterdam Study (mean age 70.5 years, 56.8% women), who visited the research center for blood sampling between 2002 and 2005. Plasma levels of 591 well-expressed circulatory miRNAs were measured by the HTG EdgeSeq Whole Transcriptome Assay, while t-tau, NfL, Aβ-40 and Aβ-42 were analysed using the Simoa NF-light® and N3PA assays. We used linear regression models to determine associations between circulatory miRNAs and markers of neurodegeneration, while adjusting for potential confounders. To account for the high-dimensional structure of miRNAs, we repeated the analysis using elastic net regularization models. Finally, we performed a post-hoc in-silico analysis to study the common miRNAs between all four biomarkers, their potential target genes and their link to dementia.
Results:
We found 58 miRNAs significantly associated with t-tau, 96 miRNAs with NfL, 158 miRNAs with Aβ-40, and 83 miRNAs with Aβ-42 (all with false discovery rate (FDR)-adjusted p-value ≤ 0.05). Notably, twelve miRNAs (miR-3141, miR-7107-5p, miR-146a-5p, miR-6887-5p, miR-221-3p, miR-4681, miR-6810-3p, miR-6821-5p, miR-654-5p, miR-4486, miR-4478, miR-326) were shared among all four neurodegeneration biomarkers. Subsequent in-silico analysis showed that many of these miRNAs are expressed across various brain regions, where they have important putative target genes (e.g., SORT1, TSPAN14, ADAM17, KLF16, WDR12). A pathway analysis highlighted the Notch signalling cascade, with possible implications for the amyloid precursor protein (APP).
Conclusions:
This population-based study revealed many circulatory miRNAs associated with biomarkers of neurodegeneration, including 12 miRNAs that were common to all, potentially offering valuable insights into regulatory pathways underlying dementia. These miRNAs could be valuable for monitoring dementia and developing effective diagnostic or therapeutic strategies.
Insights
Circulating microRNAs (miRNAs) are linked to neurodegeneration markers like tau and amyloid beta before dementia onset. Twelve specific miRNAs were common across all markers, offering potential diagnostic and therapeutic insights.
Area of Science:
- Neuroscience
- Genetics
- Biochemistry
Background:
- MicroRNAs (miRNAs) are small non-coding RNAs regulating gene expression.
- The association between circulatory miRNAs and pre-clinical dementia biomarkers remains unclear.
Purpose of the Study:
- To investigate the relationship between plasma miRNAs and neurodegeneration markers (neurofilament light chain (NfL), total tau (t-tau), amyloid beta (Aβ)) in dementia-free individuals.
- To identify specific miRNAs associated with these biomarkers and explore their potential role in dementia.
Main Methods:
- Analysis of plasma samples from 1959 dementia-free participants (Rotterdam Study).
- Measurement of 591 circulatory miRNAs using HTG EdgeSeq Whole Transcriptome Assay.
- Quantification of t-tau, NfL, Aβ-40, and Aβ-42 using Simoa assays.
- Statistical analysis using linear regression and elastic net regularization models.
Main Results:
- Significant associations found between numerous miRNAs and t-tau, NfL, Aβ-40, and Aβ-42.
- Twelve miRNAs were consistently associated with all four neurodegeneration biomarkers.
- In-silico analysis revealed these shared miRNAs target genes in brain regions and are linked to pathways like Notch signaling and APP.
Conclusions:
- Circulatory miRNAs are significantly associated with pre-clinical markers of neurodegeneration.
- The 12 common miRNAs may serve as valuable indicators for dementia risk and progression.
- These findings suggest potential for novel diagnostic or therapeutic strategies targeting miRNA pathways in dementia.
