Matrix metalloproteinase-9 inhibition prevents aquaporin-4 depolarization-mediated glymphatic dysfunction in Parkinson’s disease

Schematic representation of proposed mechanisms. In PD, active–MMP–9 is released infiltrates sites of the perivascular region, and cleaves the extracellular domain of β–DG, resulting in structural instability of the BM–astrocyte endfeet and AQP4 depolarization and glymphatic system dysfunction. The inhibition of MMP–9 prevents AQP4 depolarization–mediated glymphatic dysfunction and partially alleviates metabolic perturbations and DAergic neuron degeneration. [Display omitted] •AQP4 depolarization is a key factor responsible for glymphatic dysfunction in PD.•Abnormal MMP-9 activation triggers β-DG cleavage in PD.•This cleavage regulates glymphatic function via AQP4 polarization.•MMP-9 inhibition restored AQP4 polarization and basement membrane-astrocyte endfeet contact.•MMP-9 inhibition may serve as a potential target for enhancing glymphatic in PD. The glymphatic system offers a perivascular pathway for the clearance of pathological proteins and metabolites to optimize neurological functions. Glymphatic dysfunction plays a pathogenic role in Parkinson's disease (PD); however, the molecular mechanism of glymphatic dysfunction in PD remains elusive. To explore whether matrix metalloproteinase-9 (MMP-9)-mediated β-dystroglycan (β-DG) cleavage is involved in the regulation of aquaporin-4 (AQP4) polarity-mediated glymphatic system in PD. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD and A53T mice were used in this study. The glymphatic function was evaluated using ex vivo imaging. TGN-020, an AQP4 antagonist, was administered to investigate the role of AQP4 in glymphatic dysfunction in PD. GM6001, an MMP-9 antagonist, was administered to investigate the role of the MMP-9/β-DG pathway in regulating AQP4. The expression and distribution of AQP4, MMP-9, and β-DG were assessed using western blotting, immunofluorescence, and co-immunoprecipitation. The ultrastructure of basement membrane (BM)-astrocyte endfeet was detected using transmission electron microscopy. Rotarod and open-field tests were performed to evaluate motor behavior. Perivascular influx and efflux of cerebral spinal fluid tracers were reduced in MPTP-induced PD mice with impaired AQP4 polarization. AQP4 inhibition aggravated reactive astrogliosis, glymphatic drainage restriction, and dopaminergic neuronal loss in MPTP-induced PD mice. MMP-9 and cleaved β-DG were upregulated in both MPTP-induced PD and A53T mice, with reduced polarized localization of β-DG and AQP4 to astrocyte endfee