Temporal changes in neuroinflammation and brain glucose metabolism in a rat model of viral vector-induced α-synucleinopathy

Crabbé, Melissa; Perren, Anke Van der; Kounelis, Savannah; Lavreys, Thomas; Bormans, Guy; Baekelandt, Veerle; Casteels, Cindy; Laere, Koen Van

doi:10.1016/j.expneurol.2019.112964

Cited by 11 publications

(12 citation statements)

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“…We previously demonstrated that α-synucleinopathy is associated with higher displaceable [ 18 F]DPA-714 binding in the unilateral SN, from 28 to 42 days into the disease pathology (Crabbe et al, 2019). TSPO overexpression was shown to predominantly mark activated microglia of the pro-inflammatory phenotype (Beckers et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

“…In the overexpression model, rats received stereotactic injections of recombinant adeno-associated viral vector (rAAV2/7) encoding human A53T α-synuclein or enhanced green fluorescent protein (eGFP) into the unilateral substantia nigra (SN, right hemisphere). In conjunction with behavioral analysis, rats were sacrificed at 4 days, 2, 4, 6, and 9 weeks post-injection, based on previous analysis of disease progression and in vivo [ 18 F]FDG PET studies (Crabbe et al, 2019). Respective controls were included for every group and time point.…”

Section: Methodsmentioning

confidence: 99%

“…Sections from the α-SYN group belong to the same cohort as reported in a previous [ 18 F]DPA-714 ARX study (Crabbe et al, 2019). Therefore [ 18 F]DPA-714 results of α-SYN rats were not re-analyzed in this study.…”

Section: Methodsmentioning

confidence: 99%

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Increased P2X7 Receptor Binding Is Associated With Neuroinflammation in Acute but Not Chronic Rodent Models for Parkinson’s Disease

et al. 2019

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The purinergic P2X7 receptor is a key mediator in (neuro)inflammation, a process that is associated with neurodegeneration and excitotoxicity in Parkinson’s disease (PD). Recently, P2X7 imaging has become possible with [ 11 C]JNJ-(54173)717. We investigated P2X7 availability, in comparison with availability of the translocator protein (TSPO), in two well-characterized rat models of PD using in vitro autoradiography at multiple time points throughout the disease progression. Rats received either a unilateral injection with 6-hydroxydopamine (6-OHDA) in the striatum, or with recombinant adeno-associated viral vector overexpressing human A53T alpha-synuclein (α-SYN) in the substantia nigra. Transverse cryosections were incubated with [ 11 C]JNJ-717 for P2X7 or [ 18 F]DPA-714 for TSPO. [ 11 C]JNJ-717 binding ratios were transiently elevated in the striatum of 6-OHDA rats at day 14–28 post-injection, with peak P2X7 binding at day 14. This largely coincided with the time course of striatal [ 18 F]DPA-714 binding which was elevated at day 7–21, with peak TSPO binding at day 7. Increased P2X7 availability co-localized with microglial, but not astrocyte or neuronal markers. In the chronic α-SYN model, no significant differences were found in P2X7 binding, although in vitro TSPO overexpression was reported previously. This first study showed an increased P2X7 availability in the acute PD model in a time window corresponding with elevated TSPO binding and motor behavior changes. In contrast, the dynamics of TSPO and P2X7 were divergent in the chronic α-SYN model where no P2X7 changes were detectable. Overall, extended P2X7 phenotyping is warranted prior to implementation of P2X7 imaging for monitoring of neuroinflammation.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Increased P2X7 Receptor Binding Is Associated With Neuroinflammation in Acute but Not Chronic Rodent Models for Parkinson’s Disease

et al. 2019

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“…The 18F-FDG PET/CT scanning is an effective approach in measuring cerebral glucose metabolism to elucidate potential brain-behavior relationships in animal models of human disease [ 45 ]. It has been shown that some kinds of brain insults result in cerebral glucose hypermetabolism [ 46 , 47 ]. In the present study, we observed that the 18F-FDG uptake rate of hippocampal region in the surgery group was significantly increased when compared with the control group, indicating that surgical trauma induced postoperative glucose hypermetabolism in hippocampus.…”

Section: Discussionmentioning

confidence: 99%

Metabolic reprogramming mediates hippocampal microglial M1 polarization in response to surgical trauma causing perioperative neurocognitive disorders

Luo

Wang

Cui

et al. 2021

J Neuroinflammation

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Background Microglial polarization toward pro-inflammatory M1 phenotype are major contributors to the development of perioperative neurocognitive disorders (PNDs). Metabolic reprogramming plays an important role in regulating microglial polarization. We therefore hypothesized that surgical trauma can activate microglial M1 polarization by metabolic reprogramming to induce hippocampal neuroinflammation and subsequent postoperative cognitive impairment. Methods We used aged mice to establish a model of PNDs, and investigated whether surgical trauma induced metabolic reprograming in hippocampus using PET/CT and GC/TOF–MS based metabolomic analysis. We then determined the effect of the glycolytic inhibitor 2-deoxy-d-glucose (2-DG) on hippocampal microglial M1 polarization, neuroinflammation, and cognitive function at 3 d after surgery. Results We found that surgery group had less context-related freezing time than either control or anesthesia group (P < 0.05) without significant difference in tone-related freezing time (P > 0.05). The level of Iba-1 fluorescence intensity in hippocampus were significantly increased in surgery group than that in control group (P < 0.05) accompanied by activated morphological changes of microglia and increased expression of iNOS/CD86 (M1 marker) in enriched microglia from hippocampus (P < 0.05). PET/CT and metabolomics analysis indicated that surgical trauma provoked the metabolic reprogramming from oxidative phosphorylation to glycolysis in hippocampus. Inhibition of glycolysis by 2-DG significantly alleviated the surgical trauma induced increase of M1 (CD86+CD206−) phenotype in enriched microglia from hippocampus and up-regulation of pro-inflammatory mediators (IL-1β and IL-6) expression in hippocampus. Furthermore, glycolytic inhibition by 2-DG ameliorated the hippocampus dependent cognitive deficit caused by surgical trauma. Conclusions Metabolic reprogramming is crucial for regulating hippocampal microglial M1 polarization and neuroinflammation in PNDs. Manipulating microglial metabolism might provide a valuable therapeutic strategy for treating PNDs.

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“…In rodents, many current studies used viral overexpression of aSyn or the administration of pre-formed aSyn fibrils [42,[61][62][63]. Viral overexpression induces aSyn aggregates, degeneration of dopaminergic neurons and a behavioral phenotype [64,65]. The validity of aSyn overexpression is supported by the fact that PD can be caused by triplications of the aSyn locus and that polymorphisms in the aSyn promoter region (which affect aSyn expression levels) are important risk factors for Significances from t-test; n = 3 independent experiments.…”

Section: Open Questions and Future Perspectivesmentioning

confidence: 99%

Parkinson’s disease and translational research

Dinter¹,

Saridaki²,

Diederichs³

et al. 2020

Transl Neurodegener

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Parkinson’s disease (PD) is diagnosed when patients exhibit bradykinesia with tremor and/or rigidity, and when these symptoms respond to dopaminergic medications. Yet in the last years there was a greater recognition of additional aspects of the disease including non-motor symptoms and prodromal states with associated pathology in various regions of the nervous system. In this review we discuss current concepts of two major alterations found during the course of the disease: cytoplasmic aggregates of the protein α-synuclein and the degeneration of dopaminergic neurons. We provide an overview of new approaches in this field based on current concepts and latest literature. In many areas, translational research on PD has advanced the understanding of the disease but there is still a need for more effective therapeutic options based on the insights into the basic biological phenomena.

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Temporal changes in neuroinflammation and brain glucose metabolism in a rat model of viral vector-induced α-synucleinopathy

Cited by 11 publications

References 58 publications

Increased P2X7 Receptor Binding Is Associated With Neuroinflammation in Acute but Not Chronic Rodent Models for Parkinson’s Disease

Increased P2X7 Receptor Binding Is Associated With Neuroinflammation in Acute but Not Chronic Rodent Models for Parkinson’s Disease

Metabolic reprogramming mediates hippocampal microglial M1 polarization in response to surgical trauma causing perioperative neurocognitive disorders

Parkinson’s disease and translational research

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