Metalloproteinase-9 contributes to inflammatory glia activation and nigro-striatal pathway degeneration in both mouse and monkey models of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinsonism.

Abstract : Inflammation is a predominant aspect of neurodegenerative diseases, manifested by glia activation and expression of pro-inflammatory mediators. Studies on animal models of Parkinson's disease (PD) suggest that sustained neuroinflammation exacerbates degeneration of the dopaminergic (DA) nigro-striatal pathway. Therefore, insights into the inflammatory mechanisms of PD may help the development of novel therapeutic strategies against this disease. As extracellular matrix metalloproteinases (MMPs) could be major players in the progression of Parkinsonism, we investigated, in the substantia nigra and striatum of mice acutely injected with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), changes in mRNA expression, protein levels, and cell localization of MMP-9. This protease is mainly neuronal, but early after MPTP injection its mRNA and protein levels, as well as the number of MMP-9-expressing microglia and astrocytes, increase concomitantly to a prominent inflammation. Neuroinflammation and MMP-9(+) glia begin to decline within 2 weeks, although protein levels remain higher than control, in association with a partial recovery of DA nigro-striatal circuit. Comparable quantitative studies on MMP-9 knock-out mice, show a significant decrease in both glia activation and loss of DA neurons and fibers, with respect to wild-type. Moreover, in a parallel study on chronically MPTP-injected macaques, we observed that perpetuation of inflammation and high levels of MMP-9 are associated to DA neuron loss. Our data suggest that MMP-9 released by injured neurons favors glia activation; glial cells in turn reinforce their reactive state via autocrine MMP-9 release, contributing to nigro-striatal pathway degeneration. Specific modulation of MMP-9 activity may, therefore, be a strategy to ameliorate harmful inflammatory outcomes in Parkinsonism.
Type de document :
Article dans une revue
Brain Structure and Function, Springer Verlag, 2015, 220 (2), pp.703-27. 〈10.1007/s00429-014-0718-8〉
Liste complète des métadonnées

Littérature citée [63 références]  Voir  Masquer  Télécharger

https://hal-riip.archives-ouvertes.fr/pasteur-01180891
Contributeur : Istituto Pasteur Fondazione Cenci Bolognetti <>
Soumis le : mardi 28 juillet 2015 - 14:10:52
Dernière modification le : lundi 5 février 2018 - 15:22:13
Document(s) archivé(s) le : jeudi 29 octobre 2015 - 11:01:05

Fichier

 Accès restreint
Fichier visible le : jamais

Connectez-vous pour demander l'accès au fichier

Identifiants

Collections

Citation

V Annese, María-Trinidad Herrero, M Di Pentima, Abel Gomez, L Lombardi, et al.. Metalloproteinase-9 contributes to inflammatory glia activation and nigro-striatal pathway degeneration in both mouse and monkey models of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinsonism.. Brain Structure and Function, Springer Verlag, 2015, 220 (2), pp.703-27. 〈10.1007/s00429-014-0718-8〉. 〈pasteur-01180891〉

Partager

Métriques

Consultations de la notice

78