Promising Outcomes of Original Grant:
Our fundamental hypothesis was that modulation of blood CD163+ macrophages using nanoparticles loaded with anti-inflammatory drugs could protect neurons in the brain of models of Parkinson’s disease. Indeed, when we used such an approach, less neurons died after a neurotoxin injection into the model brain, and the animals exhibited less motor defects related to the brain lesion. Furthermore, the use of targeted nanoparticles allowed us to minimize the dose of the anti-inflammatory drug, which reduced the side effects commonly observed with higher therapeutic doses.
Objectives for Supplemental Investigation:
Our data supports a role for the CD163 macrophagic population in the disease progression. Therefore, in this experiment, we will further characterize the cells that we have targeted using both human samples and models of the disease. We will analyze the status of the CD163 macrophagic population during the disease in order to gain knowledge important for designing our future therapeutic strategy. In parallel we will deplete the macrophagic CD163 population in models to analyze their role during dopaminergic neurodegeneration. Finally, we will further test the neuroprotective potential of our approach in an alpha-synuclein based model of Parkinson’s disease.
Importance of This Research for the Development of a New PD Therapy:
The possibility of targeting a subpopulation of peripheral cells in blood that can travel to brain and exert their neuroprotective role in the area of degeneration opens possibilities. This research may lead to design of novel nanoparticles loaded with drugs that can more elegantly and specifically help the neurons in brain while avoiding toxicity.
CD163-positive macrophages -- immune cells with the CD163 protein on their surface -- may play a role in the immune response related to Parkinson's disease (PD). We found an increased number of the CD163-positive macrophages in the brain of pre-clinical models of PD. Furthermore, analysis of blood samples from people with PD supports the involvement of the CD163-positive macrophages in the disease.
In another set of experiments, we either killed these cells or deactivated them with anti-inflammatory drugs in the brain of pre-clinical models of Parkinson's. This reduced brain damage in these models. We are currently working on repeating these experiments in another pre-clinical model.
Targeting immune cells outside of the brain to treat brain disease associated with inflammation is an attractive therapeutic strategy worthy of further research.
Tentillier N, Etzerodt A, Olesen MN, et al. Anti-inflammatory modulation of microglia via CD163-targeted glucocorticoids protects dopaminergic neurons in the 6-OHDA Parkinson's disease model. J Neurosci. 2016;36(36):9375-9390.
- Poster at Gordon Conference 2015 (July). Anti-inflammatory therapy via CD163-macrophages in the 6-OHDA Parkinson's disease model
- Poster at SFN 2015. Study of the CD163 receptor in Parkinson's disease: a prospective biomarker?
- Poster at EuroGlia Meeting 2015 (July, Bilbao, Spain). Study of the CD163 receptor in Parkinson's disease: a prospective biomarker?
Invited speaker in the annual meeting for the Danish Society for Immunology, 2015: Peripheral macrophages in Parkinson's Disease: a focus on CD163