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

Abstract

Parkinson's disease (PD) patients harbour seeding competent 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 pre-formed 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 five days resulted in deteriorated grip strength and formation of phosphorylated α-syn inclusions in the brain two months later, whereas dopaminergic neuron levels were not affected. These results point towards 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.Significance statementAlthough it is well known that seeding competent alpha-synuclein (α-syn) is present in cerebrospinal fluid (CSF) of Parkinson's disease (PD) patients, the CSF-spreading of pre-formed fibrils (PFF) and the following short- and long-term consequences on the brain have not yet been investigated. Here, we show that repeated PFF administration in CSF of wild-type mice results in PD-like pathology two months later, underlining the pathologic relevance of the presence of seeding competent α-syn PFF in the CSF. Furthermore, we identify the choroid plexus (ChP), an often-neglected brain region, as a potentially important player in PD pathology due to its capability to interact with CSF α-syn.