Microglia depletion prior to lipopolysaccharide and paraquat treatment differentially modulates behavioral and neuronal outcomes in wild type and G2019S LRRK2 knock-in mice
| Autor: | Chris Rudyk, Shawn Hayley, Hongyu Sun, Sheryl Beauchamp, Nathalie Legancher, Zach Dwyer, Anu Dinesh, Michael G. Schlossmacher, Clint, Jawaria Abdali, Divya Situt |
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| Rok vydání: | 2020 |
| Předmět: |
medicine.medical_specialty
LPS Substantia nigra Neurosciences. Biological psychiatry. Neuropsychiatry Biology Stress 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Paraquat Internal medicine Full Length Article CX3CR1 medicine Toxicant Neurodegeneration Parkinson’s Cytokine Neuroinflammation 030304 developmental biology General Environmental Science 0303 health sciences Microglia Pars compacta Wild type LRRK2 medicine.disease medicine.anatomical_structure Endocrinology chemistry General Earth and Planetary Sciences 030217 neurology & neurosurgery RC321-571 |
| Zdroj: | Brain, Behavior, & Immunity-Health Brain, Behavior, & Immunity-Health, Vol 5, Iss, Pp 100079-(2020) |
| ISSN: | 2666-3546 |
| Popis: | Background Substantial data have implicated microglial-driven neuroinflammation in Parkinson’s disease (PD) and environmental toxicants have been long expected as triggers of such inflammatory processes. Of course, these environmental insults act in the context of genetic vulnerability factors and in this regard, leucine rich repeat kinase 2 (LRRK2), may play a prominent role. Methods We used a double hit, lipopolysaccharide (LPS; endotoxin) followed by paraquat (pesticide toxicant) model of PD in mice with the most common LRRK2 mutation G2019S, knockin mice and wild type littermates. In order to assess the contribution of microglia, we depleted these cells (through 14 days of the CSF-1 antagonist, PLX-3397) prior to LPS and paraquat exposure. Results We found that the G2019S mice displayed the greatest signs of behavioral pathology, but that the PLX-3397 induced microglial depletion at the time of LPS exposure diminished toxicity and weight loss and blunted the reduction in home-cage activity with subsequent paraquat exposure. However, neither the PLX-3397 pre-treatment nor the G2019S mutation affected the LPS + paraquat induced loss of substantia nigra pars compacta (SNc) dopamine neurons or elevation of circulating immune (IL-6) or stress (corticosterone) factors. Intriguingly, microglial morphological ratings were basally enhanced in G2019S mice and the PLX-3397 pre-treatment reversed this effect. Moreover, PLX-3397 pre-treatment selectively elevated soluble a-synuclein and SIRT3 levels, while reducing SNc caspase-1 and 3, along with CX3CR1. Hence, the re-populated “new” microglia following cessation of PLX-3397 clearly had an altered phenotype or were immature at the time of sacrifice (i.e. after 11 days). Conclusions Collectively, these findings suggest that G2019S knock-in and PLX-3397 microglial depletion at the time of LPS exposure affects behavioral, but not neurodegenerative responses to subsequent environmental toxin exposure. Highlights • The G2019S LRRK2 mutant augmented behavioral pathology, but not substantia nigra pars compacta (SNc) dopamine neuron loss. • PLX-3397 induced microglial depletion diminished toxicity and behavioral changes with subsequent paraquat exposure. • Re-populated “new” microglia following PLX-3397 had an altered phenotype or were immature at the time of sacrifice. • The G2019S knock-in and PLX-3397 microglial depletion affected behavioral, but not neurodegenerative responses. |
| Databáze: | OpenAIRE |
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