Brain-derived exosomes from dementia with Lewy bodies propagate α-synuclein pathology

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Abstract

Proteins implicated in neurodegenerative conditions such as Alzheimer’s disease (AD) and Dementia with Lewy Bodies (DLB) have been identified in bodily fluids encased in extracellular vesicles called exosomes. Whether exosomes found in DLB patients can transmit pathology is not clear. In this study, exosomes were successfully harvested through ultracentrifugation from brain tissue from DLB and AD patients as well as non-diseased brain tissue. Exosomes extracted from brains diagnosed with either AD or DLB contained aggregate-prone proteins. Furthermore, injection of brain-derived exosomes from DLB patients into the brains of wild type mice induced α-synuclein (α-syn) aggregation. As assessed through immunofluorescent double labeling, α-syn aggregation was observed in MAP2 ⁺, Rab5 ⁺ neurons. Using a neuronal cell line, we also identified intracellular α-syn aggregation mediated by exosomes is dependent on recipient cell endocytosis. Together, these data suggest that exosomes from DLB patients are sufficient for seeding and propagating α-syn aggregation in vivo.

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Classification and basic pathology of Alzheimer disease.

Charles Duyckaerts, Benoît Delatour, Marie-Claude Potier (2009)

The lesions of Alzheimer disease include accumulation of proteins, losses of neurons and synapses, and alterations related to reactive processes. Extracellular Abeta accumulation occurs in the parenchyma as diffuse, focal or stellate deposits. It may involve the vessel walls of arteries, veins and capillaries. The cases in which the capillary vessel walls are affected have a higher probability of having one or two apoepsilon 4 alleles. Parenchymal as well as vascular Abeta deposition follows a stepwise progression. Tau accumulation, probably the best histopathological correlate of the clinical symptoms, takes three aspects: in the cell body of the neuron as neurofibrillary tangle, in the dendrites as neuropil threads, and in the axons forming the senile plaque neuritic corona. The progression of tau pathology is stepwise and stereotyped from the entorhinal cortex, through the hippocampus, to the isocortex. The neuronal loss is heterogeneous and area-specific. Its mechanism is still discussed. The timing of the synaptic loss, probably linked to Abeta peptide itself, maybe as oligomers, is also controversial. Various clinico-pathological types of Alzheimer disease have been described, according to the type of the lesions (plaque only and tangle predominant), the type of onset (focal onset), the cause (genetic or sporadic) and the associated lesions (Lewy bodies, vascular lesions, hippocampal sclerosis, TDP-43 inclusions and argyrophilic grain disease).

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Interaction and uptake of exosomes by ovarian cancer cells

Cristina Escrevente, Sascha Keller, Peter Altevogt … (2011)

Background Exosomes consist of membrane vesicles that are secreted by several cell types, including tumors and have been found in biological fluids. Exosomes interact with other cells and may serve as vehicles for the transfer of protein and RNA among cells. Methods SKOV3 exosomes were labelled with carboxyfluoresceine diacetate succinimidyl-ester and collected by ultracentrifugation. Uptake of these vesicles, under different conditions, by the same cells from where they originated was monitored by immunofluorescence microscopy and flow cytometry analysis. Lectin analysis was performed to investigate the glycosylation properties of proteins from exosomes and cellular extracts. Results In this work, the ovarian carcinoma SKOV3 cell line has been shown to internalize exosomes from the same cells via several endocytic pathways that were strongly inhibited at 4°C, indicating their energy dependence. Partial colocalization with the endosome marker EEA1 and inhibition by chlorpromazine suggested the involvement of clathrin-dependent endocytosis. Furthermore, uptake inhibition in the presence of 5-ethyl-N-isopropyl amiloride, cytochalasin D and methyl-beta-cyclodextrin suggested the involvement of additional endocytic pathways. The uptake required proteins from the exosomes and from the cells since it was inhibited after proteinase K treatments. The exosomes were found to be enriched in specific mannose- and sialic acid-containing glycoproteins. Sialic acid removal caused a small but non-significant increase in uptake. Furthermore, the monosaccharides D-galactose, α-L-fucose, α-D-mannose, D-N-acetylglucosamine and the disaccharide β-lactose reduced exosomes uptake to a comparable extent as the control D-glucose. Conclusions In conclusion, exosomes are internalized by ovarian tumor cells via various endocytic pathways and proteins from exosomes and cells are required for uptake. On the other hand, exosomes are enriched in specific glycoproteins that may constitute exosome markers. This work contributes to the knowledge about the properties and dynamics of exosomes in cancer.

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Induction of α-synuclein aggregate formation by CSF exosomes from patients with Parkinson’s disease and dementia with Lewy bodies

Anne Stuendl, Marcel Kunadt, Niels Kruse … (2015)

Stuendl et al. show that CSF exosomes of patients with Parkinson’s disease or dementia with Lewy bodies contain α-synuclein and induce α-synuclein aggregation in a reporter cell line. Thus, exosomes may support inter-neuronal transmission of α-synuclein pathology. CSF exosomal α-synuclein may serve as a biomarker in α-synuclein-related neurodegeneration.

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Author and article information

Contributors

Robert A. Rissman: 858-246-0140 , rrissman@ucsd.edu

Journal

Journal ID (nlm-ta): Acta Neuropathol Commun

Journal ID (iso-abbrev): Acta Neuropathol Commun

Title: Acta Neuropathologica Communications

Publisher: BioMed Central (London )

ISSN (Electronic): 2051-5960

Publication date (Electronic): 9 June 2017

Publication date PMC-release: 9 June 2017

Publication date Collection: 2017

Volume: 5

Electronic Location Identifier: 46

Affiliations

[1 ]ISNI 0000 0001 2107 4242, GRID grid.266100.3, Department of Neurosciences, , UCSD School of Medicine, ; La Jolla, CA 92093 USA

[2 ]ISNI 0000 0001 2107 4242, GRID grid.266100.3, Department of Pathology, , UCSD School of Medicine, ; La Jolla, CA 92093 USA

[3 ]ISNI 0000 0004 0419 2708, GRID grid.410371.0, , Veterans Affairs San Diego Healthcare System, ; San Diego, CA 92161 USA

Article

Publisher ID: 445

DOI: 10.1186/s40478-017-0445-5

PMC ID: 5466770

PubMed ID: 28599681

SO-VID: ad918fcf-0f48-4fa6-a7e6-13f9234d8e46

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Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 27 March 2017

Date accepted : 20 May 2017

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100000049, National Institute on Aging;

Award ID: AG051848

Award ID: AG0051839

Award ID: AG005131

Award ID: AG018440

Award ID: AG0002016

Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;

Award ID: BX003040

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Keywords: alzheimer’s disease,exosomes,alpha synuclein,lewy body,tau,amyloid beta,dementia

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Keywords: alzheimer’s disease, exosomes, alpha synuclein, lewy body, tau, amyloid beta, dementia

Brain-derived exosomes from dementia with Lewy bodies propagate α-synuclein pathology

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Most cited references 16

Classification and basic pathology of Alzheimer disease.

Interaction and uptake of exosomes by ovarian cancer cells

Induction of α-synuclein aggregate formation by CSF exosomes from patients with Parkinson’s disease and dementia with Lewy bodies

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