The influence of the glymphatic system on α-synuclein propagation: the role of aquaporin-4

Abstract

Propagation and aggregation of prion proteins, such as tau and α-synuclein (αSyn), are key pathological features of neurodegenerative diseases. Extracellular clearance pathways, such as the glymphatic system, may play a crucial role in the removal of these toxic proteins from the brain. Primarily active during sleep, this system relies on aquaporin-4 (AQP4) water channel expression and polarisation to astrocytic endfeet, facilitating interstitial solute clearance. Glymphatic dysfunction has recently been implicated in Parkinson's disease, however the precise mechanisms underlying the pathogenic effect of this dysfunction remain unclear. This includes how impaired glymphatic function influences αSyn propagation dynamics, and the role of propagating αSyn itself on glymphatic function. In this study, we used a mouse model of αSyn propagation to elucidate the impact of αSyn aggregation on glymphatic function, by measuring CSF-ISF exchange and assessing AQP4 and associated endfoot complex proteins in the brain over time and across different regions. Our results show that direct injection of αSyn pre-formed fibrils leads to local reduced expression of the AQP4 endfoot complex, but propagation of αSyn pathology induces an enhancement of glymphatic function suggesting compensatory upregulation in response to increasing αSyn aggregate load. To determine the influence of glymphatic dysfunction on αSyn propagation dynamics, we then employed a pharmacological approach to inhibit glymphatic function in this model. Acute glymphatic inhibition significantly reduced brain to CSF clearance of misfolded αSyn, and chronic treatment exacerbated αSyn pathology, cerebral atrophy, and motor behavioural deficits in mice. Together our findings show that αSyn clearance and propagation are modulated by glymphatic function. Moreover, they suggest that AQP4 complex dysregulation may contribute to glymphatic impairment associated with Parkinson's diseases, supporting further mechanistic investigation of this protein complex in the disease.

Keywords: Parkinson’s; alpha-synuclein; aquaporin-4; glymphatic; propagation.