Integrin CD11b mediates locus coeruleus noradrenergic neurodegeneration in a mouse Parkinson’s disease model

Hou, Liyan; Qu, Xingyue; Qiu, Xiaofei; Huang, Ruixue; Zhao, Xianxian; Wang, Qingshan

doi:10.1186/s12974-020-01823-3

Cited by 27 publications

(14 citation statements)

References 48 publications

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“…The midbrain areas were quickly dissected from mice after perfusion with PBS and the total RNA was purified by using Trizol reagents. RNA was reversely transcribed with MuLV reverse transcriptase and oligo dT primers [ 18 , 19 , 29 ]. SYBR Green Premix and Takara Thermal Cycler Dice Real Time System were used for real-time PCR amplification.…”

Section: Methodsmentioning

confidence: 99%

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

Ruan

Zhang

Huang

et al. 2022

IJMS

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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.

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Section: Methodsmentioning

confidence: 99%

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

Ruan

Zhang

Huang

et al. 2022

IJMS

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“…Immunohistochemistry was performed based on a previous protocol. 36 , 37 Briefly, mice were perfused transcardially with PBS and then with 4% paraformaldehyde (PFA). The brains were then postfixed with 4% PFA at 4 °C for 48 h. The brains were dehydrated with 30% sucrose in PBS for an additional 2 days.…”

Section: Methodsmentioning

confidence: 99%

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

Lu¹,

Hou²,

Zhang³

et al. 2021

JIR

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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.

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“…21 Moreover, CD11b deficiency reduced microglial proinflammatory activation in a mouse model of Parkinson's disease. 71 However, CD11b-staining coverage was not significantly altered by LPS or CyPPA. Similarly, mRNA expression analyses of the microglial reactivity marker CD68 did not reveal significant changes.…”

mentioning

confidence: 88%

SK-Channel Activation Alters Peripheral Metabolic Pathways in Mice, but Not Lipopolysaccharide-Induced Fever or Inflammation

Bredehöft¹,

Dolga²,

Honrath³

et al. 2022

JIR

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Purpose Previously, we have shown that CyPPA (cyclohexyl-[2-(3,5-dimethyl-pyrazol-1-yl)-6-methyl-pyrimidin-4-yl]-amine), a pharmacological small-conductance calcium-activated potassium (SK)–channel positive modulator, antagonizes lipopolysaccharide (LPS)-induced cytokine expression in microglial cells. Here, we aimed to test its therapeutic potential for brain-controlled sickness symptoms, brain inflammatory response during LPS-induced systemic inflammation, and peripheral metabolic pathways in mice. Methods Mice were pretreated with CyPPA (15 mg/kg IP) 24 hours before and simultaneously with LPS stimulation (2.5 mg/kg IP), and the sickness response was recorded by a telemetric system for 24 hours. A second cohort of mice were euthanized 2 hours after CyPPA or solvent treatment to assess underlying CyPPA-induced mechanisms. Brain, blood, and liver samples were analyzed for inflammatory mediators or nucleotide concentrations using immunohistochemistry, real-time PCR and Western blot, or HPLC. Moreover, we investigated CyPPA-induced changes of UCP1 expression in brown adipose tissue (BAT)–explant cultures. Results CyPPA treatment did not affect LPS-induced fever, anorexia, adipsia, or expression profiles of inflammatory mediators in the hypothalamus or plasma or microglial reactivity to LPS (CD11b staining and CD68 mRNA expression). However, CyPPA alone induced a rise in core body temperature linked to heat production via altered metabolic pathways like reduced levels of adenosine, increased protein content, and increased UCP1 expression in BAT-explant cultures, but no alteration in ATP/ADP concentrations in the liver. CyPPA treatment was accompanied by altered pathways, including NFκB signaling, in the hypothalamus and cortex, while circulating cytokines remained unaltered. Conclusion Overall, while CyPPA has promise as a treatment strategy, in particular according to results from in vitro experiments, we did not reveal anti-inflammatory effects during severe LPS-induced systemic inflammation. Interestingly, we found that CyPPA alters metabolic pathways inducing short hyperthermia, most likely due to increased energy turnover in the liver and heat production in BAT.

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Integrin CD11b mediates locus coeruleus noradrenergic neurodegeneration in a mouse Parkinson’s disease model

Cited by 27 publications

References 48 publications

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

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

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

SK-Channel Activation Alters Peripheral Metabolic Pathways in Mice, but Not Lipopolysaccharide-Induced Fever or Inflammation

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