Abstract
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.
Highlights
Alzheimer’s disease (AD) is a progressive neurodegenerative disease mainly affecting the elderly population and accounting for 60–80% of dementia cases [1]
We showed that tumor necrosis factor (TNF) signaling is induced in the choroid plexus (CP) of AD patients and AD mouse models, whereas TNF receptor 1 (TNFR1) abrogation reduced brain inflammation, blood–cerebrospinal fluid (CSF) barrier impairment and Aβ oligomers (AβO)-induced memory impairment [14]
During disease progression (7 weeks of age), we observed higher levels of particles in amyloid precursor protein (APP)/PS1 mice compared to age-matched non-transgenic littermates, while levels normalized at later stages (Fig. 1a, b, Additional file 1: Figure S1A–D)
Summary
Alzheimer’s disease (AD) is a progressive neurodegenerative disease mainly affecting the elderly population and accounting for 60–80% of dementia cases [1]. The choroid plexus epithelial (CPE) cells form the blood–CSF barrier and provide an active interface between the CSF and the blood. Dysfunction of the brain barriers occurs in a number of neurological diseases, including AD [8, 9]. The pathophysiological changes in the choroid plexus (CP) lead to impaired clearing of Aβ from the CSF, thereby further aggravating the disease pathology. Accumulating evidence supports the notion that compromised blood–CSF barrier function and diminished clearance of Aβ from the CSF exacerbates AD pathology by elevating CSF Aβ levels [11,12,13]. We reported that the intracerebroventricular (icv) injection of Aβ1–42 oligomers (AβO) induces inflammation in the CP as well as in the hippocampus and increases the expression of matrix metalloproteinases (MMPs) leading to blood–CSF barrier disruption [4]. We showed that tumor necrosis factor (TNF) signaling is induced in the CP of AD patients and AD mouse models, whereas TNF receptor 1 (TNFR1) abrogation reduced brain inflammation, blood–CSF barrier impairment and AβO-induced memory impairment [14]
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