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Published on: March 11, 2020
Plasma inflammatory biomarkers for Huntington's disease patients and mouse model
Kuo-Hsuan Chang1, Yih-Ru Wu1, Yi-Chun Chen1
1Department of Neurology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan.
Insights
Huntington's disease (HD) patients show altered plasma inflammatory markers like IL-6 and VEGF, potentially serving as biomarkers for disease onset and progression. These findings may guide future therapeutic targets for HD.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- Huntington's disease (HD) involves striatal and cortical neuron degeneration, with neuroinflammation, particularly microglial activation, implicated in its pathogenesis.
- The huntingtin (HTT) protein is expressed in peripheral inflammatory cells, suggesting peripheral inflammatory markers may reflect neuroinflammation in HD patients.
Purpose of the Study:
- To investigate peripheral plasma inflammatory markers as potential biomarkers for Huntington's disease (HD) onset and progression.
- To correlate plasma inflammatory marker levels with clinical assessments and disease progression in a mouse model.
Main Methods:
- Examined plasma levels of 13 microglia-derived inflammatory markers in human HD patients and healthy controls.
- Assessed plasma inflammatory marker levels in the R6/2 mouse model of HD at various ages.
- Correlated plasma IL-6 levels with the UHDRS independence scale and functional capacity in HD patients.
Main Results:
- HD patients exhibited significantly increased plasma levels of IL-6, MMP-9, VEGF, and TGF-β1, and decreased IL-18 compared to controls.
- Plasma IL-6 levels inversely correlated with functional capacity in HD patients.
- In R6/2 mice, altered plasma levels of VEGF, IL-6, MMP-9, TGF-β1, and IL-18 were observed, correlating with disease progression stages.
Conclusions:
- Altered plasma inflammatory marker profiles in HD patients and the R6/2 mouse model suggest their potential as biomarkers for HD.
- These inflammatory markers represent potential therapeutic targets for drug development in Huntington's disease.
Abstract:
Huntington's disease (HD), caused by expanded CAG repeats encoding a polyglutamine tract in the huntingtin (HTT) protein, presents with a predominant degeneration of neurons in the striatum and cortex. Lines of evidence have observed neuroinflammation, particularly microglial activation, is involved in the pathogenesis of HD. Given that HTT is also expressed in peripheral inflammatory cells, it is possible that inflammatory changes detected in peripheral plasma may be biologically relevant and parallel the neuroinflammatory process of HD patients. By examining the expression levels of 13 microglia-derived inflammatory markers in the plasma of 5 PreHD carriers, 15 HD patients and 16 healthy controls, we found plasma levels of IL-6, MMP-9, VEGF and TGF-β1 were significantly increased in HD patients when compared with the controls, while plasma level of IL-18 were significantly reduced in HD patients compared with controls. Plasma level of IL-6 was reversely correlated with the UHDRS independence scale and functional capacity. To understand the temporal correlation between these inflammatory markers and HD progression, their levels were further tested in plasma from R6/2 mouse HD model at different ages. In rotarod test, R6/2 HD mice started to manifest HD phenotype at 7.5 weeks of age. Higher plasma VEGF levels of R6/2 mice than those of age-matched wild-type (WT) littermates were noted from 7 (presymptomatic stage) to 13 weeks of age (late symptomatic stage). The plasma IL-6 levels of R6/2 mice were higher than those of the WT littermates from 9 (early symptomatic stage) to 13 weeks of age. R6/2 mice demonstrated higher MMP-9 and TGF-β1 levels than their WT littermates from 11 (middle symptomatic stage) to 13 weeks of age. In contrast, the plasma IL-18 level was lower than those in WT littermates since 11 weeks of age. These altered expressions of inflammatory markers may serve as the potential biomarkers for HD onset and progression. Specific inhibition/activation of these inflammatory markers may be the targets of HD drug development.
