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Detection of MicroRNAs in Microglia by Real-time PCR in Normal CNS and During Neuroinflammation
Published on: July 23, 2012
Microglia-Derived Extracellular Vesicles from Alzheimer's Disease Patients Carry miRNAs Driving a Neuroinflammatory
Skaiste Arbaciauskaite1,2, Simona Silvestri3,4,5, Pingyan Luo6
1Neuroscience Research Center, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Zu Berlin and Berlin Institute of Health, 10117, Berlin, Germany. skaiste.arbaciauskaite@charite.de.
Abstract:
Alzheimer's disease (AD) represents the most common cause of dementia and urgently requires sensitive biomarkers and effective therapies. Extracellular vesicles represent membranous nano-sized particles secreted from cells, which serve as intercellular messengers participating in central nervous system (CNS) homeostasis, but also are implicated in AD pathogenesis. In addition, EVs containing disease-specific signatures, such as microRNAs (miRNAs), are considered as potent tools for the diagnosis and treatment of AD and other brain disorders. In this study, we used TMEM119 antibody to immunocapture microglia-derived EVs from cerebrospinal fluid (CSF) of AD patients and control subjects. EVs harvested from these CSF samples contained distinct disease-specific miRNA profiles, as assessed by small RNA sequencing. Using a HEK TLR reporter cell system, we found that these miRNA are potent activators of human TLR8, an established RNA sensor. Out of the miRNAs present in AD-associated EVs, selected oligonucleotides were synthesized and loaded into BV2 microglia-derived EVs. Exposure of primary murine microglia to these miRNA-loaded EVs led to TNF release from these cells, thereby driving a neuroinflammatory response. Taken together, putatively microglia-derived EVs from the CSF of AD patients contain miRNAs, which are capable of activating hTLR8 and inducing an inflammatory response from microglia.
Insights
Microglia-derived extracellular vesicles in Alzheimer's disease (AD) cerebrospinal fluid contain microRNAs that activate TLR8 and trigger neuroinflammation. This finding offers potential diagnostic and therapeutic targets for AD.
Area of Science:
- Neuroscience
- Biochemistry
- Immunology
Background:
- Alzheimer's disease (AD) is the leading cause of dementia, necessitating novel biomarkers and treatments.
- Extracellular vesicles (EVs) are intercellular messengers involved in CNS homeostasis and AD pathogenesis.
- MicroRNAs (miRNAs) within EVs are potential diagnostic and therapeutic tools for brain disorders.
Purpose of the Study:
- To investigate microglia-derived EVs in AD cerebrospinal fluid (CSF).
- To identify miRNA profiles within these EVs and their functional consequences.
- To explore the role of these miRNAs in activating immune responses.
Main Methods:
- Immunocapture of microglia-derived EVs from AD patient and control CSF using TMEM119 antibody.
- Small RNA sequencing to analyze miRNA profiles.
- HEK TLR reporter cell system to assess miRNA activation of TLR8.
- Synthesis and loading of selected miRNAs into BV2 microglia-derived EVs.
- Exposure of primary murine microglia to miRNA-loaded EVs to measure TNF release.
Main Results:
- CSF microglia-derived EVs showed distinct disease-specific miRNA profiles in AD patients.
- These miRNAs potently activated human Toll-like receptor 8 (TLR8).
- Microglia exposed to miRNA-loaded EVs released TNF, indicating a neuroinflammatory response.
Conclusions:
- Microglia-derived EVs from AD CSF harbor miRNAs capable of activating TLR8.
- These miRNAs can induce a neuroinflammatory response in microglia, contributing to AD pathogenesis.
- This study highlights a potential mechanism linking EVs, miRNAs, and neuroinflammation in Alzheimer's disease.
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