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Transmission of α-synuclein-containing erythrocyte-derived extracellular vesicles across the blood-brain barrier via adsorptive mediated transcytosis: another mechanism for initiation and progression of Parkinson’s disease?

Authors
  • Matsumoto, Junichi1
  • Stewart, Tessandra1
  • Sheng, Lifu1
  • Li, Na2
  • Bullock, Kristin3
  • Song, Ning1
  • Shi, Min1
  • Banks, William A3, 4
  • Zhang, Jing1, 2
  • 1 University of Washington School of Medicine, Department of Pathology, Seattle, WA, 98104, USA , Seattle (United States)
  • 2 Peking University Health Science Centers, Department of Pathology, Beijing, 100191, China , Beijing (China)
  • 3 Geriatrics Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, 98108, USA , Seattle (United States)
  • 4 University of Washington School of Medicine, Division of Gerontology and Geriatric Medicine, Department of Medicine, Seattle, WA, 98108, USA , Seattle (United States)
Type
Published Article
Journal
Acta Neuropathologica Communications
Publisher
Springer (Biomed Central Ltd.)
Publication Date
Sep 13, 2017
Volume
5
Issue
1
Identifiers
DOI: 10.1186/s40478-017-0470-4
Source
Springer Nature
Keywords
License
Green

Abstract

Parkinson’s disease (PD) pathophysiology develops in part from the formation, transmission, and aggregation of toxic species of the protein α-synuclein (α-syn). Recent evidence suggests that extracellular vesicles (EVs) may play a vital role in the transport of toxic α-syn between brain regions. Moreover, increasing evidence has highlighted the participation of peripheral molecules, particularly inflammatory species, which may influence or exacerbate the development of PD-related changes to the central nervous system (CNS), although detailed characterization of these species remains to be completed. Despite these findings, little attention has been devoted to erythrocytes, which contain α-syn concentrations ~1000-fold higher than the cerebrospinal fluid, as a source of potentially pathogenic α-syn. Here, we demonstrate that erythrocytes produce α-syn-rich EVs, which can cross the BBB, particularly under inflammatory conditions provoked by peripheral administration of lipopolysaccharide. This transport likely occurs via adsorptive-mediated transcytosis, with EVs that transit the BBB co-localizing with brain microglia. Examination of microglial reactivity upon exposure to α-syn-containing erythrocyte EVs in vitro and in vivo revealed that uptake provoked an increase in microglial inflammatory responses. EVs derived from the erythrocytes of PD patients elicited stronger responses than did those of control subjects, suggesting that inherent characteristics of EVs arising in the periphery might contribute to, or even initiate, CNS α-syn-related pathology. These results provide new insight into the mechanisms by which the brain and periphery communicate throughout the process of synucleinopathy pathogenesis.

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