Microglial Activation Damages Dopaminergic Neurons through MMP-2/-9-Mediated Increase of Blood-Brain Barrier Permeability in a Parkinson's Disease Mouse Model.

Ruixue Huang,Liyan Hou,Zhengzheng Ruan,Wei Sun,Jie Zhao,Qingshan Wang,Dongdong Zhang

doi:10.3390/ijms23052793

Ruixue Huang, Liyan Hou + Show 5 more

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https://doi.org/10.3390/ijms23052793

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Abstract

Chronic neuroinflammation has been considered to be involved in the progressive dopaminergic neurodegeneration in Parkinson’s disease (PD). However, the mechanisms remain unknown. Accumulating evidence indicated a key role of the blood–brain barrier (BBB) dysfunction in neurological disorders. This study is designed to elucidate whether chronic neuroinflammation damages dopaminergic neurons through BBB dysfunction by using a rotenone-induced mouse PD model. Results showed that rotenone dose-dependently induced nigral dopaminergic neurodegeneration, which was associated with increased Evans blue content and fibrinogen accumulation as well as reduced expressions of zonula occludens-1 (ZO-1), claudin-5 and occludin, three tight junction proteins for maintaining BBB permeability, in mice, indicating BBB disruption. Rotenone also induced nigral microglial activation. Depletion of microglia or inhibition of microglial activation by PLX3397 or minocycline, respectively, greatly attenuated BBB dysfunction in rotenone-lesioned mice. Mechanistic inquiry revealed that microglia-mediated activation of matrix metalloproteinases-2 and 9 (MMP-2/-9) contributed to rotenone-induced BBB disruption and dopaminergic neurodegeneration. Rotenone-induced activation of MMP-2/-9 was significantly attenuated by microglial depletion and inactivation. Furthermore, inhibition of MMP-2/-9 by a wide-range inhibitor, SB-3CT, abrogated elevation of BBB permeability and simultaneously increased tight junctions expression. Finally, we found that microglial depletion and inactivation as well as inhibition of MMP-2/-9 significantly ameliorated rotenone-elicited nigrostriatal dopaminergic neurodegeneration and motor dysfunction in mice. Altogether, our findings suggested that microglial MMP-2/-9 activation-mediated BBB dysfunction contributed to dopaminergic neurodegeneration in rotenone-induced mouse PD model, providing a novel view for the mechanisms of Parkinsonism.

Highlights

Chronic exposure to environmental toxins is closely associated with the pathogenesis of Parkinson’s disease (PD) that is characterized by neuronal damage in the nigrostriatal system and formation of Lewy bodies in the surviving dopaminergic neurons [1]
Our results suggested that microglial activation-mediated blood–brain barrier (BBB) disruption via MMP-2/-9 contributed to dopaminergic neurodegeneration in rotenone-treated mice, providing a novel mechanistic insight for rotenone-elicited neurotoxicity and related Parkinsonism
The following salient features were found: (1) rotenone dose-dependently induced BBB dysfunction; (2) rotenone exposure stimulated microglial activation and microglial depletion or inactivation attenuated rotenone-induced BBB disruption; (3) elevated activation of MMP-2/-9 were observed in rotenone-injected mice, which was significantly dampened through depletion and inactivation of microglia; (4) inhibition of MMP-2/-9 by SB-3CT abrogated rotenone-induced BBB disruption; and (5) microglial depletion, inactivation, or inhibition of MMP-2/-9 attenuated loss of dopaminergic neurons and gait abnormality in rotenone-treated mice

Summary

Introduction

Chronic exposure to environmental toxins is closely associated with the pathogenesis of Parkinson’s disease (PD) that is characterized by neuronal damage in the nigrostriatal system and formation of Lewy bodies in the surviving dopaminergic neurons [1]. Human studies revealed that chronic exposure to rotenone pesticide significantly elevated the risk of PD [2]. Experimental rodents intoxicated with rotenone recapitulated the typical features of PD, such as degeneration of nigral dopaminergic neurons, aggregation of αsynuclein, the main component of Lewy bodies, and motor deficits [3]. The exact mechanism of PD remains unclear, strong evidence revealed a critical role of chronic neuroinflammation mediated by brain innate immune microglia cells in dopaminergic neurodegeneration [4,5]. Postmortem studies in patients with PD showed amounts of activated microglia around the damaged dopaminergic neurons [6]. How microglia-mediated neuroinflammation damages dopaminergic neurons remains to be elucidated currently

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