EV secretion at the blood–cerebrospinal fluid interface in the pathogenesis of Alzheimer’s disease

Increasing evidence indicates that extracellular vesicles (EVs) play an important role in the pathogenesis of Alzheimer’s disease (AD). Researchers from the VIB Center for Inflammation Research 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, the researchers studied the importance of CP-mediated EV release in AD pathogenesis. They 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, the researchers 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.

Fig. 7

As a mouse model for Alzheimer’s disease (AD), we injected amyloid beta oligomers (AβO) into the cerebrospinal fluid (CSF) of wild-type (WT) mice via their left lateral brain ventricle (i.e. intracerebroventricular (icv) injection) (Panel A). This resulted in an increased release of extracellular vesicles (EVs) into the CSF, whereby these EVs are at least in part derived from the choroid plexus (CP) (Panel B). Interestingly, AβO-induced, CP-derived EVs carry several pro-inflammatory proteins including the complement protein C3. Furthermore, we could show that the AβO-induced, CP-derived EVs exert a pro-inflammatory response on brain target cells in vitro (panel D). Strikingly, these EVs also play a role in loss of cognitive function (panel C), since blocking the EV secretion using GW4869 protected against the AβO-induced cognitive decline. Image created with BioRender

Vandendriessche C, Balusu S, Van Cauwenberghe C. et al. (2021) Importance of extracellular vesicle secretion at the blood–cerebrospinal fluid interface in the pathogenesis of Alzheimer’s disease. acta neuropathol commun 9, 143 [article]

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