Loss of cannabinoid receptor 2 promotes α-Synuclein-induced microglial synaptic pruning in nucleus accumbens by modulating the pCREB-c-Fos signaling pathway and complement system

Feng, Linjuan; Lo, Hsuan; You, Hanlin; Wu, Wei; Cheng, Xinbin; Xin, Jiawei; Ye, Zucheng; Chen, Xiaochun; Pan, Xiaodong

doi:10.1016/j.expneurol.2022.114230

Cited by 6 publications

(8 citation statements)

References 48 publications

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“…In vitro, coated PM were fixed in 4% paraformaldehyde for 30 min. Both brain slices and cells were incubated with glycine median and treated with primary and secondary antibodies (Table S3) as previously reported (Feng et al, 2023). The image was acquired with ZEISS 780 confocal and the quantification of the protein co‐localized in microglia was assessed with ZEN 3.1 (blue edition) software.…”

Section: Methodsmentioning

confidence: 99%

“…As previously described (Feng et al, 2023), the transgenic mice (aged 12 weeks old) received bilateral stereotaxic injections of fibrillar α-Syn (1 μg/site) and saline (vehicle control group), at a total of 0.5 μL volume per hemisphere, into the striatum at a rate of 0.01 uL/min with a 2.5 μL Hamilton syringe (32G needle) using the following coordinates (from bregma): anterior = +0.8 mm, lateral = ±2.0 mm from midline, depth = À2.2 mm (from dura). Antibiotics and analgesics were smeared at the surface of the wound of each mouse.…”

Section: Stereotaxic Surgery and Tissue Preparationmentioning

confidence: 99%

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Microglial LRRK2‐mediated NFATc1 attenuates α‐synuclein immunotoxicity in association with CX3CR1‐induced migration and the lysosome‐initiated degradation

Feng

Hong

et al. 2023

Glia

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Synucleinopathies refer to a range of neurodegenerative diseases caused by abnormal α-synuclein (α-Syn) deposition, including Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). Their pathogenesis is strongly linked to microglial dysfunction and neuroinflammation, which involves the leucine-rich-repeat kinase 2 (LRRK2)-regulated nuclear factor of activated T-cells (NFAT). Of the NFAT family, NFATc1 has been found to be increasingly translocated into the nucleus in α-syn stimulation. However, the specific role of NFATc1-mediated intracellular signaling in PD remains elusive in regulating microglial functions. In the current study, we crossbred LRRK2 or NFATc1 conditional knockout mice with Lyz2 Cre mice to generate mice with microglia-specific deletion of LRRK2 or NFATc1, and by stereotactic injection of fibrillary α-Syn, we generated PD models in these mice. We found that LRRK2 deficiency enhanced microglial phagocytosis in the mice after α-Syn exposure and that genetic inhibition of NFATc1 markedly diminished phagocytosis and α-Syn elimination. We further demonstrated that LRRK2 negatively regulated NFATc1 in α-Syn-treated microglia, in which microglial LRRK2-deficiency facilitated NFATc1 nuclear translocation, CX3CR1 upregulation, and microglia migration. Additionally, NFATc1 translocation upregulated the expression of Rab7 and promoted the formation of late lysosomes, resulting in α-Syn degradation. In contrast, the microglial NFATc1 deficiency impaired CX3CR1 upregulation and the formation of Rab7-mediated late lysosomes. These findings highlight the critical role of NFATc1 in modulating microglial migration and phagocytosis, in which the LRRK2-NFATc1 signaling pathway regulates the expression of microglial CX3CR1 and endocytic degradative Rab7 to attenuate α-synuclein immunotoxicity.

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Section: Methodsmentioning

confidence: 99%

Section: Stereotaxic Surgery and Tissue Preparationmentioning

confidence: 99%

Microglial LRRK2‐mediated NFATc1 attenuates α‐synuclein immunotoxicity in association with CX3CR1‐induced migration and the lysosome‐initiated degradation

Feng

Hong

et al. 2023

Glia

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“…In the context of aggregated Asyn, only one other study has evaluated the role of CB2 in Asyn clearance and found opposing effects on Asyn accumulation. Feng and colleagues evaluated transgenic CB2-deficient and CB2 wild-type mice treated with human Asyn pre-formed fibrils (PFF) in the nucleus accumbens and found increased area coverage of Asyn 2 hours post-PFF injections in the absence of CB2 (21). Although the study suggests impaired Asyn clearance, authors also report increased intensity of CD68 immunostaining and morphologically more ameboid (less branches) shaped IBA1+ microglia in CB2-/- compared to wild-type mice at the same timepoint, both of which would suggest phagocytic microglial phenotypes.…”

Section: Discussionmentioning

confidence: 99%

“…Our results support that CB2 plays a role in microglial response and phenotype. A previous study reported that CB2-deficient microglia display shorter projections that are less ramified within 24 hours after Asyn PFF injections relative to CB2 wild-type microglia as measured by a rigorous Scholl analysis (21). Although, we sampled adequately throughout the nigra, our data did not show statistically significant differences in the size of IBA1+ cell bodies when evaluated by IHC at 8-weeks, yet our flow cytometry data does suggest that microglia exhibited a stronger activation profile as shown by the elevated CD11b expression.…”

Section: Discussionmentioning

confidence: 99%

“…Non-selective cannabinoid receptor agonists also ameliorate neurotoxin-induced neuroinflammation and neurodegeneration in PD animal models (16, 20). Yet, only one report, using genetic deletion approaches, has evaluated the role of CB2 on the clearance of Asyn aggregates in brain (21), and there has not yet been a study evaluating CB2-selective ligands on Asyn burden in vivo .…”

Section: Introductionmentioning

confidence: 99%

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Modulation of cannabinoid receptor 2 alters neuroinflammation and reduces formation of alpha-synuclein aggregates in a rat model of nigral synucleinopathy

Joers,

Murray,

McLaughlin

et al. 2023

Preprint

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There is growing evidence that neuroinflammation accompanies and may promote progression of alpha-synuclein (Asyn)-induced nigral dopaminergic (DA) degeneration. Research into the disequilibrium of microglial phenotypes has become an area of intense focus in neurodegenerative disease as a potential mechanism that contributes to chronic neuroinflammation and neuronal loss in Parkinson’s disease (PD). From a therapeutic perspective, development of immunomodulatory strategies that dampen overproduction of pro-inflammatory cytokines from chronically activated immune cells and induce a pro-phagocytic phenotype is expected to promote Asyn removal and protect vulnerable neurons. Cannabinoid receptor-2 (CB2) is highly expressed on activated microglia and peripheral immune cells, is upregulated in the substantia nigra of PD patients and in mice models of nigral degeneration. Furthermore, modulation of CB2 protects against rotenone-induced nigral degeneration, however CB2 has not been pharmacologically and selectively targeted in an alpha-synuclein focused model of PD. We find that 7 weeks of peripheral SMM-189 treatment reduced phosphorylated (pSer129) alpha-synuclein in the substantia nigra compared to vehicle treatment. Additionally, SMM-189 altered brain immune cell phenotypes with increased CD68 and decreased CD163 protein expression, elevated wound healing immune mediator gene expression and modified leukocyte infiltration kinetics as determined by flow cytometry. Additionally, peripheral immune cells increased wound healing non-classical monocytes and decreased pro-inflammatory classical monocytes. Together, results suggest that targeting CB2 with SMM-189 biased immune cell function toward a phagocytic phenotype and reduced toxic species of alpha-synuclein aggregation. This study highlights that CB2 may be a target for proteinopathies with notable accompanying inflammation.

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Effect of Early Inhibition of Toll-Like Receptor 4 on Hippocampal Plasticity in a Neonatal Rat Model of Hypoxic-Ischemic Brain Damage

Li,

Ouyang,

Zhang

et al. 2024

Mol Neurobiol

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Loss of cannabinoid receptor 2 promotes α-Synuclein-induced microglial synaptic pruning in nucleus accumbens by modulating the pCREB-c-Fos signaling pathway and complement system

Cited by 6 publications

References 48 publications

Microglial LRRK2‐mediated NFATc1 attenuates α‐synuclein immunotoxicity in association with CX3CR1‐induced migration and the lysosome‐initiated degradation

Microglial LRRK2‐mediated NFATc1 attenuates α‐synuclein immunotoxicity in association with CX3CR1‐induced migration and the lysosome‐initiated degradation

Modulation of cannabinoid receptor 2 alters neuroinflammation and reduces formation of alpha-synuclein aggregates in a rat model of nigral synucleinopathy

Effect of Early Inhibition of Toll-Like Receptor 4 on Hippocampal Plasticity in a Neonatal Rat Model of Hypoxic-Ischemic Brain Damage

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