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Alteration of miRNAs in Small Neuron-Derived Extracellular Vesicles of Alzheimer's Disease Patients and the Effect of Extracellular Vesicles on Microglial Immune Responses

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Abstract

Alzheimer's disease (AD) is one of the most severe neurodegenerative diseases observed in the elderly population. Although the hallmarks of AD have been identified, the methods for its definitive diagnosis and treatment are still lacking. Extracellular vesicles (EVs) have become a promising source for biomarkers since the identification of their content. EVs are released from multiple cell types and, when released from neurons, they pass from the brain to the blood with their cargo molecules. Hence, neuron-specific EV-resident microRNAs (miRNAs) are promising biomarkers for diagnosis of AD. This study aimed to identify altered miRNA content in small neuron-derived extracellular vesicles (sNDEVs) isolated from AD patients and healthy individuals. Furthermore, we examined the role of sNDEV-resident miRNAs in neuron-glia cellular interaction to understand their role in AD propagation. We identified 10 differentially expressed miRNAs in the sNDEVs of patients via next-generation sequencing and validated the most dysregulated miRNA, let-7e, with qRT-PCR. Let-7e was significantly increased in the sNDEVs of AD patients compared with those of healthy controls in a larger cohort. First, we evaluated the diagnostic utility of let-7e via ROC curve analysis, which revealed an AUC value of 0.9214. We found that IL-6 gene expression was increased in human microglia after treatment with sNDEVs of AD patients with a high amount of let-7e. Our study suggests that sNDEV-resident let-7e is a potential biomarker for AD diagnosis, and that AD patient-derived sNDEVs induce a neuroinflammatory response in microglia.

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Data Availability Statement

The data sets generated during and/or analyzed during the current study are available from the corresponding author upon reasonable request.

Abbreviations

AD :

Alzheimer's disease

Aβ :

Amyloid beta

APP :

Amyloid precursor protein

AUC :

Area under the curve

BACE1 :

Beta-secretase 1

cDNA :

Complementary DNA

CNS :

Central nervous system

CSF :

Cerebrospinal fluid

EV :

Extracellular vesicle

GO :

Gene ontology

HC :

Healthy control

IL :

Interleukin

KEGG :

Kyoto Encyclopedia of Genes and Genomes

L1CAM :

Neural cell adhesion protein

miRNA :

MicroRNA

MISEV :

Minimal information for studies of extracellular vesicles

MMSE :

Mini-Mental State Exam

MRI :

Magnetic resonance imaging

mRNA :

Messenger RNA

sNDEV :

Small neuron-derived extracellular vesicle

NGS :

Next-generation sequencing

NTA :

Nanoparticle tracking analysis

PET :

Positron emission tomography

ROC :

Receiver operating characteristic

sEVs :

Small extracellular vesicles

TEM :

Transmission electron microscopy

TLR :

Toll-like receptor

TNF :

Tumor necrosis factor

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Acknowledgements

The authors would like to thank Dr. Ben Cathcart for his critical reading of the manuscript, IBG Optical Imaging Core facility members, and Genc Laboratory research technician Nilsu Askin for their contribution.

Funding

This study was financially supported by The Scientific and Technological Research Council of Turkey (TUBITAK, Project No: 217S584).

Author information

Authors and Affiliations

  1. Biomedicine and Genome Center, Izmir, Turkey

    Devrim Yagmur Durur, Bora Tastan, Melis Olcum, Hamdiye Uzuner, Gökhan Karakülah & Sermin Genc

  2. Izmir International Biomedicine and Genome Institute, Dokuz Eylul University Health Campus, Izmir, Turkey

    Devrim Yagmur Durur, Bora Tastan, Hamdiye Uzuner, Gökhan Karakülah & Sermin Genc

  3. Vocational School of Health Services, Izmir Democracy University, Izmir, Turkey

    Kemal Ugur Tufekci

  4. Department of Neuroscience, Health Science Institute, Dokuz Eylul University, Izmir, Turkey

    Gorsev Yener & Sermin Genc

  5. Department of Neurology, Faculty of Medicine, Izmir University of Economics, Izmir, Turkey

    Gorsev Yener

Authors
  1. Devrim Yagmur Durur
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  2. Bora Tastan
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  3. Kemal Ugur Tufekci
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  4. Melis Olcum
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  7. Gorsev Yener
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  8. Sermin Genc
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Contributions

SG and GY designed the study. DYD, BT, MO designed and performed the experiments. DYD, BT, KUT, HU, GK, GY, and SG analyzed and interpreted the data. DYD, BT, KUT, and SG wrote the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Sermin Genc.

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Ethics Approval

The study was carried out according to the principles of the Declaration of Helsinki, and it was approved by the clinical research ethics committee of Dokuz Eylul University (approval date: August 21, 2017; protocol number: 399-SBKAEK).

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Written informed consents were provided by all the patients or legal custodians and the healthy controls.

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The authors declare that no competing interests could be construed as a potential conflict of interest.

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Durur, D.Y., Tastan, B., Ugur Tufekci, K. et al. Alteration of miRNAs in Small Neuron-Derived Extracellular Vesicles of Alzheimer's Disease Patients and the Effect of Extracellular Vesicles on Microglial Immune Responses. J Mol Neurosci 72, 1182–1194 (2022). https://doi.org/10.1007/s12031-022-02012-y

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