Background Huntington’s disease (HD) is an inherited devastating neurodegenerative disorder with no treatment to slow down the disease progression available. HD is well-characterised by widespread changes in CNS and systemic alterations as well. Immune dysfunction outside the CNS is increasingly recognised as a substantial modulator of HD progression. To study the long-term changes in early disease course we have created a unique model of HD, a minipig transgenic for human mutant huntingtin.
Aims (i) to define the role of innate immune activation in HD, (ii) to monitor the levels of inflammatory proteins during HD progress
Methods Age-matched TgHD and WT minipigs with similar genetic background and before the onset of clinical symptoms were utilised in this study. Sera from a set of F3 generation animals were collected. The expression of selected inflammatory proteins was examined by targeted proteomic profiling using Luminex xMAP and quantitative ELISA immunoassay. For assessment of functional complement activity we applied a qualitative determination using Wieslab Complement system Screenkit. As complementary approach the levels of cytokines secreted by monocytes were studied.
Results Our results proved the most striking difference in the level of chemokine IL-8 between TgHD and WT minipigs at the age of 8–16 months. The concentration of the anti-inflammatory cytokine IL-4 increased at the age of 16–24 months. We also identified in vitrohyperactivity of immune cells responding to inflammatory stimulus in TgHD animals with altered production of mainly IL-8. The preliminary data showed activation of the complement system.
Conclusion HD is slowly progressive and changes in immune markers are subtle. The changes in pre-manifest stadium identified in our HD model can obtain accessible non-invasive indicators of disease progress and with further validation might become a potential biomarker candidate.
Support CHDI Foundation, TA01011466, CZ.1.05/2.1.00/03.0124, RVO 67985904.