PXD021665

PXD021665 is an original dataset announced via ProteomeXchange.

Title	Importance of choroid plexus-mediated extracellular vesicle secretion in the pathogenesis of Alzheimer’s disease
Description	Alzheimer’s disease (AD) is a major neurodegenerative disease characterized by extracellular amyloid β (Aβ) plaques and intracellular hyperphosphorylated tau (P-tau). Increasing evidence indicates that extracellular vesicles (EVs) play an important role in AD pathogenesis. We previously reported that the choroid plexus epithelial (CPE) cells, present at the interface between blood and cerebrospinal fluid (CSF), show increased secretion of EVs into the CSF in response to peripheral inflammation. Here, we studied the importance of CP-derived EVs in AD pathogenesis. We observed increased EV levels in the CSF of 7 weeks old transgenic APP/PS1 mice, correlating with higher Aβ CSF levels at this age, while levels normalized with age. To study whether the elevated Aβ CSF levels might be responsible for this increase, mice were intracerebroventricularly (icv) injected with Aβ oligomers (AβO) which revealed a significant increase in the amount of CD9 and CD81 positive EVs in the CSF. The importance of the CPE cells as EV source was shown by in vitro analysis of AβO stimulated primary CPE cells and in vivo analysis of the CP by transmission electron microscopy (TEM). Evaluation of EV marker immunostaining, both from AβO icv injected mice and APP/PS1 mice, confirmed the upregulation of EV biogenesis in the CP. Interestingly, AβO-induced, CP-derived EVs induced pro-inflammatory effects in mixed cortical cultures (MCC) whereas proteome analysis revealed the presence of complement protein C3, amongst other inflammatory proteins. Additionally, we could show for the first time that AβO induce an upregulation of C3 in CPE cells. These data highlight the CP and CP-derived, C3-containing EVs as novel players in the emerging importance of the complement pathway in the pathogenesis of AD. Strikingly, inhibition of EV production using GW4869 resulted in protection against the AβO-induced cognitive decline. In conclusion, our results show that intraventricular AβO induce both C3 activation and EV secretion by the CP and that these EVs contain pro-inflammatory molecules, including C3, which play a role in neuroinflammation and loss of cognition. This suggests that inhibition of EV production by the CP might be an interesting therapeutic approach to be explored in the prevention or treatment of AD.
HostingRepository	PRIDE
AnnounceDate	2021-09-09
AnnouncementXML	Submission_2021-09-09_08:28:34.761.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Teresa Mendes Maia
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	acetylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2020-09-24 01:24:08	ID requested
⏵ 1	2021-09-09 08:28:35	announced

Vandendriessche C, Balusu S, Van Cauwenberghe C, Brkic M, Pauwels M, Plehiers N, Bruggeman A, Dujardin P, Van Imschoot G, Van Wonterghem E, Hendrix A, Baeke F, De Rycke R, Gevaert K, Vandenbroucke RE, Importance of extracellular vesicle secretion at the blood-cerebrospinal fluid interface in the pathogenesis of Alzheimer's disease. Acta Neuropathol Commun, 9(1):143(2021) [pubmed]

submitter keyword: EV,Alzheimer, choroid plexus, CSF,AβO

Roosmarijn E. Vandenbroucke
contact affiliation	VIB Center for Inflammation Research, VIB, Ghent, Belgium Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
contact email	roosmarijn.vandenbroucke@irc.vib-ugent.be
lab head
Teresa Mendes Maia
contact affiliation	VIB Proteomics Core
contact email	teresa.maia@vib-ugent.be
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD021665
     1. Label: PRIDE project
     2. Name: Importance of choroid plexus-mediated extracellular vesicle secretion in the pathogenesis of Alzheimer’s disease