Plasma Exosomal miRNAs in Persons with and without Alzheimer Disease: Altered Expression and Prospects for Biomarkers

Lugli, Giovanni; Cohen, Aaron M.; Bennett, David A.; Shah, Raj C.; Fields, Christopher J.; Hernandez, Alvaro G.; Smalheiser, Neil R.

doi:10.1371/journal.pone.0139233

Cited by 358 publications

(277 citation statements)

References 45 publications

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“…Pathological proteins or miRNAs in exosomes have emerged as potential biomarkers for AD and other neurodegenerative diseases [34, 51, 52]. A recent study demonstrated the presence of Tau in exosomes isolated from blood of patients with AD or frontotemporal dementia (FTD) and that the exosomal levels of total Tau and Tau phosphorylated at T181 or S396 for AD and FTD were significantly higher than in control subjects [51].…”

Section: Discussionmentioning

confidence: 99%

The release and trans-synaptic transmission of Tau via exosomes

Wang

Balaji

Kaniyappan

et al. 2017

Mol Neurodegeneration

554

521

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BackgroundTau pathology in AD spreads in a hierarchical pattern, whereby it first appears in the entorhinal cortex, then spreads to the hippocampus and later to the surrounding areas. Based on this sequential appearance, AD can be classified into six stages (“Braak stages”). The mechanisms and agents underlying the progression of Tau pathology are a matter of debate. Emerging evidence indicates that the propagation of Tau pathology may be due to the transmission of Tau protein, but the underlying pathways and Tau species are not well understood. In this study we investigated the question of Tau spreading via small extracellular vesicles called exosomes.MethodsExosomes from different sources were analyzed by biochemical methods and electron microscopy (EM) and cryo-EM. Microfluidic devices that allow the culture of cell populations in different compartments were used to investigate the spreading of Tau.ResultsWe show that Tau protein is released by cultured primary neurons or by N2a cells overexpressing different Tau constructs via exosomes. Neuron-derived exosomal Tau is hypo-phosphorylated, compared with cytosolic Tau. Depolarization of neurons promotes release of Tau-containing exosomes, highlighting the importance of neuronal activity. Using microfluidic devices we show that exosomes mediate trans-neuronal transfer of Tau depending on synaptic connectivity. Tau spreading is achieved by direct transmission of exosomes between neurons. In organotypic hippocampal slices, Tau-containing exosomes in conditioned medium are taken up by neurons and microglia, not astrocytes. In N2a cells, Tau assemblies are released via exosomes. They can induce inclusions of other Tau molecules in N2a cells expressing mutant human Tau. We also studied exosomes from cerebrospinal fluid in AD and control subjects containing monomeric and oligomeric Tau. Split-luciferase complementation reveals that exosomes from CSF can promote Tau aggregation in cultured cells.ConclusionOur study demonstrates that exosomes contribute to trans-synaptic Tau transmission, and thus offer new approches to control the spreading of pathology in AD and other tauopathies.Electronic supplementary materialThe online version of this article (doi:10.1186/s13024-016-0143-y) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

The release and trans-synaptic transmission of Tau via exosomes

Wang

Balaji

Kaniyappan

et al. 2017

Mol Neurodegeneration

554

521

View full text Add to dashboard Cite

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“…A recent study by Lugli et al used Illumina deep sequencing to determine differential expressions of miRNAs in plasma from patients with AD and healthy control subjects [89]. They found a total of 20 miRNAs downregulated; four miRNAs (miR-548at-5p, miR-138-5p, miR-5001-3p, and miR-659-5p) upregulated; and seven miRNAs (miR-185-5p, miR-342-3p, miR-141-3p, miR-342-5p, miR-23b-3p, miR-338-3p, and miR-3613-3p) significantly downregulated in AD patients compared to controls (Table-1).…”

Section: Circulatory Mirnas In Alzheimer’s Diseasementioning

confidence: 99%

Are circulating microRNAs peripheral biomarkers for Alzheimer's disease?

Kumar

Reddy

2016

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

248

181

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Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by memory loss, multiple cognitive abnormalities and intellectual impairments. Currently, there are no drugs or agents that can delay and/or prevent the progression of disease in elderly individuals, and there are no peripheral biomarkers that can detect AD early in its pathogenesis. Research has focused on identifying biomarkers for AD so that treatment can be begun as soon as possible in order to restrict or prevent intellectual impairments, memory loss, and other cognitive abnormalities that are associated with the disease. One such potential biomarker is microRNAs that are found in circulatory biofluids, such as blood and blood components, serum and plasma. Blood and blood components are primary sources where miRNAs are released in either cell-free form and then bind to protein components, or are in an encapsulated form with microvesicle particles. Exosomal miRNAs are known to be stable in biofluids and can be detected by high throughput techniques, like microarray and RNA sequencing. In AD brain, enriched miRNAs encapsulated with exosomes crosses the blood brain barrier and secreted in the CSF and blood circulations. This review summarizes recent studies that have identified miRNAs in the blood, serum, plasma, exosomes, cerebral spinal fluids, and extracellular fluids as potential biomarkers of AD. Recent research has revealed only six miRNAs–miR-9, miR-125b, miR-146a, miR-181c, let-7g-5p, and miR-191-5p – that were reported by multiple investigators. Some studies analyzed the diagnostic potential of these six miRNAs through receiver operating curve analysis which indicates the significant area-under-curve values in different biofluid samples. miR-191-5p was found to have the maximum area-under-curve value (0.95) only in plasma and serum samples while smaller area-under-curve values were found for miR-125, miR-181c, miR-191-5p, miR-146a, and miR-9. This article shortlisted the promising miRNA candidates and discussed their diagnostic properties and cellular functions in order to search for potential biomarker for AD.

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“…The following patients were excluded from the study: patients receiving heparin therapy at the time of the blood draws (since heparin can interfere with RNA isolation); patients who had been diagnosed with any nonAlzheimer's type of dementia; and patients suffering from other diseases, such as AMI, cancer, Parkinson's disease, and multiple sclerosis, as these diseases can cause differences in miRNA expression (Lugli et al 2015). …”

Section: Study Populationsmentioning

confidence: 99%

Lower Serum Levels of miR-29c-3p and miR-19b-3p as Biomarkers for Alzheimer’s Disease

et al. 2017

Tohoku J. Exp. Med.

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MicroRNAs (miRNAs) are short noncoding RNA that participate in posttranscriptional gene regulation. However, little is understood about the roles of miRNAs in Alzheimer's disease (AD). In this study, we used next-generation sequencing on RNA extracted from the serum samples of 20 AD patients and 20 controls, yielding a total of 72 miRNAs with significantly changed expression levels. Among these candidates, we selected 9 miRNAs with most significant alteration in disease, and validated their expression levels using RT-qPCR analysis on serum samples from 45 AD patients and 40 control subjects. Thus, the serum levels of miR-146a-5p, 106b-3p, 195-5p, 20b-5p, and 497-5p were significantly higher, while those of miR-125b-3p, 29c-3p, 93-5p and 19b-3p were significantly lower in AD patients, compared with control subjects. Two miRNAs, miR-29c-3p and miR-19b-3p, were selected because both RNA deep-sequencing and q-PCR methods indicated lower serum levels of these miRNAs in AD patients. Computational analysis predicted that 3′-untranslated region of signal transduction and activator of transcription 3 (STAT3) mRNA is targeted both by miR-29c-3p and miR-19b-3p. Using SH-SY5Y human neuroblastoma cells, we showed that transfection with miR-29c-3p or miR-19b-3p inhibitor significantly increased STAT3 phosphorylation. Furthermore, Water maze test, which assesses the learning and memory deficits in rodents, showed that escape latency was significantly shorter in AD rats with overexpression of miR-29c-3p or miR-19b-3p than in control AD rats. These results suggest that miR-29c-3p or miR-19b-3p may contribute to the cognitive function. In conclusion, the serum levels of miR-29c-3p and miR-19b-3p are helpful biomarkers for AD.

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Plasma Exosomal miRNAs in Persons with and without Alzheimer Disease: Altered Expression and Prospects for Biomarkers

Cited by 358 publications

References 45 publications

The release and trans-synaptic transmission of Tau via exosomes

The release and trans-synaptic transmission of Tau via exosomes

Are circulating microRNAs peripheral biomarkers for Alzheimer's disease?

Lower Serum Levels of miR-29c-3p and miR-19b-3p as Biomarkers for Alzheimer’s Disease

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