The Spreading and Effects of Human Recombinant α-Synuclein Preformed Fibrils in the Cerebrospinal Fluid of Mice.

Parkinson's disease (PD) patients harbor seeding-competent α-synuclein (α-syn) in their cerebrospinal fluid (CSF), which is mainly produced by the choroid plexus (ChP). Nonetheless, little is known about the role of the CSF and the ChP in PD pathogenesis. To address this question, we used an intracerebroventricular (icv) injection mouse model to assess CSF α-syn spreading and its short- and long-term consequences on the brain. Hereby, we made use of seeding-competent, recombinant α-syn preformed fibrils (PFF) that are known to induce aggregation and subsequent spreading of endogenous α-syn in stereotactic tissue injection models. Here, we show that icv-injected PFF, but not monomers (Mono), are rapidly removed from the CSF by interaction with the ChP. Additionally, shortly after icv injection both Mono and PFF were detected in the olfactory bulb and striatum. This spreading was associated with increased inflammation and complement activation in these tissues as well as leakage of the blood-CSF barrier. Despite these effects, a single icv injection of PFF didn't induce a decline in motor function. In contrast, daily icv injections over the course of 5 days resulted in deteriorated grip strength and formation of phosphorylated α-syn inclusions in the brain 2 months later, whereas dopaminergic neuron levels were not affected. These results point toward an important clearance function of the CSF and the ChP, which could mediate removal of PFF from the brain, whereby chronic exposure to PFF in the CSF may negatively impact blood-CSF barrier functionality and PD pathology.

Fighting fire with fire: The immune system might be key in our fight against Alzheimer's disease.

The ultimate cause of Alzheimer's disease (AD) is still unknown and no disease-modifying treatment exists. Emerging evidence supports the concept that the immune system has a key role in AD pathogenesis. This awareness leads to the idea that specific parts of the immune system must be engaged to ward off the disease. Immunotherapy has dramatically improved the management of several previously untreatable cancers and could hold similar promise as a novel therapy for treating AD. However, before potent immunotherapies can be rationally designed as treatment against AD, we need to fully understand the dynamic interplay between AD and the different parts of our immune system. Accordingly, here we review the most important aspects of both the innate and adaptive immune system in relation to AD pathology.

Free complement and complement containing extracellular vesicles as potential biomarkers for neuroinflammatory and neurodegenerative disorders.

The complement system is implicated in a broad range of neuroinflammatory disorders such as Alzheimer's disease (AD) and multiple sclerosis (MS). Consequently, measuring complement levels in biofluids could serve as a potential biomarker for these diseases. Indeed, complement levels are shown to be altered in patients compared to controls, and some studies reported a correlation between the level of free complement in biofluids and disease progression, severity or the response to therapeutics. Overall, they are not (yet) suitable as a diagnostic tool due to heterogeneity of reported results. Moreover, measurement of free complement proteins has the disadvantage that information on their origin is lost, which might be of value in a multi-parameter approach for disease prediction and stratification. In light of this, extracellular vesicles (EVs) could provide a platform to improve the diagnostic power of complement proteins. EVs are nanosized double membrane particles that are secreted by essentially every cell type and resemble the (status of the) cell of origin. Interestingly, EVs can contain complement proteins, while the cellular origin can still be determined by the presence of EV surface markers. In this review, we summarize the current knowledge and future opportunities on the use of free and EV-associated complement proteins as biomarkers for neuroinflammatory and neurodegenerative disorders.

Importance of extracellular vesicle 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). 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 (Aß) CSF levels at this age. The intracerebroventricular (icv) injection of Aß oligomers (AßO) in wild-type mice revealed a significant increase of EVs in the CSF, signifying that the presence of CSF-AßO 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, AßO-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 AßO-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.