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

  • J Adv Res. 2023 Mar 18;S2090-1232(23)00086-3. doi: 10.1016/j.jare.2023.03.004.
Xiaoli Si  1 ,  Shaobing Dai  2 ,  Yi Fang  3 ,  Jiahui Tang  3 ,  Zhiyun Wang  3 ,  Yaolin Li  3 ,  Zhe Song  3 ,  Ying Chen  3 ,  Yi Liu  3 ,  Guohua Zhao  4 ,  Baorong Zhang  5 ,  Jiali Pu  6
Affiliations
  • 1. Department of Neurology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310009, China; Department of Neurology, The Fourth Affiliated Hospital, International Institutes of Medicine, Zhejiang University School of Medicine, Yiwu, Zhejiang 322000, China.
  • 2. Department of Neurology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310009, China; Department of Anesthesiology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310009, China.
  • 3. Department of Neurology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310009, China.
  • 4. Department of Neurology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310009, China; Department of Neurology, The Fourth Affiliated Hospital, International Institutes of Medicine, Zhejiang University School of Medicine, Yiwu, Zhejiang 322000, China. Electronic address: [email protected].
  • 5. Department of Neurology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310009, China. Electronic address: [email protected].
  • 6. Department of Neurology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310009, China. Electronic address: [email protected].
PMID: 36940850 DOI: 10.1016/j.jare.2023.03.004
Abstract

Introduction: 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.

Objective: 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.

Methods: 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.

Results: 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 endfeet. MMP-9 inhibition restored BM-astrocyte endfeet-AQP4 integrity and attenuated MPTP-induced metabolic perturbations and dopaminergic neuronal loss.

Conclusion: AQP4 depolarization contributes to glymphatic dysfunction and aggravates PD pathologies, and MMP-9-mediated β-DG cleavage regulates glymphatic function through AQP4 polarization in PD, which may provide novel insights into the pathogenesis of PD.

Keywords
Parkinson’s disease; aquaporin-4; glymphatic system; matrix metalloproteinase-9; metabolomics.
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