Importance of extracellular vesicle secretion at the blood-cerebrospinal fluid interface in the pathogenesis of Alzheimer's disease.
Alzheimer’s disease
Blood–cerebrospinal fluid barrier
Choroid plexus
Complement
Extracellular vesicles
Journal
Acta neuropathologica communications
ISSN: 2051-5960
Titre abrégé: Acta Neuropathol Commun
Pays: England
ID NLM: 101610673
Informations de publication
Date de publication:
23 08 2021
23 08 2021
Historique:
received:
01
07
2021
accepted:
12
08
2021
entrez:
24
8
2021
pubmed:
25
8
2021
medline:
27
1
2022
Statut:
epublish
Résumé
Increasing evidence indicates that extracellular vesicles (EVs) play an important role in the pathogenesis of Alzheimer's disease (AD). We previously reported that the blood-cerebrospinal fluid (CSF) interface, formed by the choroid plexus epithelial (CPE) cells, releases an increased amount of EVs into the CSF in response to peripheral inflammation. Here, we studied the importance of CP-mediated EV release in AD pathogenesis. We observed increased EV levels in the CSF of young transgenic APP/PS1 mice which correlated with high amyloid beta (Aβ) CSF levels at this age. The intracerebroventricular (icv) injection of Aβ oligomers (AβO) in wild-type mice revealed a significant increase of EVs in the CSF, signifying that the presence of CSF-AβO is sufficient to induce increased EV secretion. Using in vivo, in vitro and ex vivo approaches, we identified the CP as a major source of the CSF-EVs. Interestingly, AβO-induced, CP-derived EVs induced pro-inflammatory effects in mixed cortical cultures. Proteome analysis of these EVs revealed the presence of several pro-inflammatory proteins, including the complement protein C3. Strikingly, inhibition of EV production using GW4869 resulted in protection against acute AβO-induced cognitive decline. Further research into the underlying mechanisms of this EV secretion might open up novel therapeutic strategies to impact the pathogenesis and progression of AD.
Identifiants
pubmed: 34425919
doi: 10.1186/s40478-021-01245-z
pii: 10.1186/s40478-021-01245-z
pmc: PMC8381545
doi:
Substances chimiques
Amyloid beta-Peptides
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
143Informations de copyright
© 2021. The Author(s).
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