Microglial Activation Mediates Noradrenergic Locus Coeruleus Neurodegeneration via Complement Receptor 3 in a Rotenone-Induced Parkinson’s Disease Mouse Model

Abstract

Background Chronic exposure to the insecticide rotenone can damage dopaminergic neurons and lead to an increased risk of Parkinson’s disease (PD). Whereas it is not clear whether rotenone induces neurodegeneration of noradrenergic locus coeruleus (LC/NE) neurons. Chronic neuroinflammation mediated by microglia has been involved in the pathogenesis of PD. Evidence shows that complement receptor 3 (CR3) is a crucial regulator of microglial activation and related neurodegeneration. However, it is not clear whether CR3 mediates rotenone-elicited degeneration of LC/NE neurons through microglia-mediated neuroinflammation. Materials and Methods Wild type (WT) and CR3 knockout (KO) mice were treated with rotenone. PLX3397 and minocycline were used to deplete or inactivate the microglia. Leukadherin-1 (LA-1) was used to modulate CR3. LC/NE neurodegeneration, microglial phenotype, and expression of CR3 were determined by using immunohistochemistry, Western blot and real-time polymerase chain reaction (PCR) techniques. The glutathione (GSH) and malondialdehyde (MDA) contents were measured by using commercial kits. Results Rotenone exposure led to dose- and time-dependent LC/NE neuronal loss and microglial activation in mice. Depletion of microglia by PLX3397 or inhibition of microglial activation by minocycline significantly reduced rotenone-induced LC/NE neurodegeneration. Mechanistic studies revealed that CR3 played an essential role in the rotenone-induced activation of microglia and neurodegeneration of LC/NE neurons. Rotenone elevated the expression of CR3, and genetic ablation of CR3 markedly reduced rotenone-induced microglial activation and M1 polarization. LA-1 also suppressed rotenone-induced toxic microglial M1 activation. Furthermore, lack of CR3 or treatment with LA-1 reduced oxidative stress in the brainstem of rotenone-intoxicated mice. Finally, we found that mice deficient in CR3 or treated with LA-1 were more resistant to rotenone-induced LC/NE neurodegeneration than WT or vehicle-treated mice, respectively. Conclusion Our results indicate that CR3-mediated microglial activation participates in rotenone-induced LC/NE neurodegeneration, providing novel insight into environmental toxin-induced neurotoxicity and related Parkinsonism.

Partial depletion and repopulation of microglia have different effects in the acute MPTP mouse model of Parkinson’s disease

“…However, controversial effects of microglia have been reported in MPTP‐, 6‐OHDA‐ or rotenone‐induced PD models. 18 , 22 , 23 , 24 To clarify the function of microglia in Parkinson's disease, in this study, we fed mice with a PLX3397‐containing diet for different days to test the efficiency of microglial depletion in the nigrostriatal pathway. Our data reveal that 21‐day treatment with PLX3397 dramatically reduced the microglial population in the substantia nigra, and had no noticeable effect on the nigrostriatal dopaminergic pathway in mice.…”

“… 22 Moreover, in rotenone‐induced mouse PD models, microglial activation contributed to neurodegeneration in the locus coeruleus and cognitive impairments. 23 , 24 Thus, whether microglia are beneficial or harmful remains controversial in PD. And the effects of repopulated microglia in PD are also warranted to illustrate.…”

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

“…Adult male C57BL/6 mice were randomly separated into control, 0.75 mg/kg/d and 1.5 mg/kg/d rotenone groups ( n = 12). Rotenone was administered to mice by intraperitoneal injection for three consecutive weeks [ 18 , 19 ]. Control mice received equal amounts of vehicle.…”

“…Rotenone at a dose of 1.5 mg/kg/d was administered as described above. Mice in the rotenone + PLX3397 group received (by gavage, daily) PLX3397 (40 mg/kg/d), a selective antagonist for CSF1R, for 7 days and then were treated every other day 30 min prior to rotenone until the end of the experiment [ 18 , 19 ]. Mice in the rotenone + minocycline group received (i.p.)…”

Modulation of Sirt1-mTORC1 Pathway in Microglia Attenuates Retinal Ganglion Cell Loss After Optic Nerve Injury

“…Recently, a colony stimulating factor 1 receptor (CSF1R) inhibitor, PLX5622, was developed to deplete >95% of all microglia in the central nervous system. 37 In Alzheimer's disease (AD), several groups have identified that PLX5622 could improve cognition in 3xTg-AD, APP-PS1 transgenic and 5xFAD mice model. [38][39][40][41] In traumatic brain injury (TBI), recent studies also have reported that PLX5622 treatment limited TBIassociated neuropathology.…”