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Characterization and Isolation of Mouse Primary Microglia by Density Gradient Centrifugation
Published on: February 16, 2018
Human microglia reduce alpha-synuclein aggregation and are neuroprotective in adult mouse brain
Katrina Albert1, Sanni Peltonen1, Anni Vanne1
1A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, 70211 Kuopio, Finland.
Abstract:
Microglia, brain-resident immune cells, are involved in pathophysiology of several neurodegenerative diseases, including Parkinson's disease. Given significant species-specific differences in microglia gene expression, particularly in disease-risk genes, as well as the highly reactive nature of these cells, studying human microglia in a whole brain environment is essential. Here, we established a humanized mouse model by transplanting human induced pluripotent stem cell-derived hematopoietic progenitor cells into the striatum of immunodeficient adult mice and injected human alpha-synuclein preformed fibrils to model Parkinson's disease pathology. Transplanted human cells engraft, mature into microglia and maintain their phenotype for at least three months post-transplantation. These human microglia interact with alpha-synuclein, significantly limiting its propagation from the striatum to the substantia nigra and further reducing local small aggregates; they also mildly protect tyrosine hydroxylase neurons there. Transcriptomic profiling reveals 56 differentially expressed genes in human microglia in response to alpha-synuclein preformed fibrils, while host mouse cells show 202 gene expression changes, including an upregulation of gene Hcrt (fold change = 7.77, p = 0.0015). Immunohistochemistry analysis further confirms the preservation of hypocretin-positive neurons in the hypothalamus of the transplanted mice (p = 0.0079). The findings highlight the neuroprotective role of human microglia and establish a more disease-relevant in vivo model for investigating alpha-synuclein aggregation and therapeutic interventions in Parkinson's disease.
Insights
Human microglia transplanted into mice effectively combat Parkinson's disease pathology by limiting alpha-synuclein spread and protecting neurons. This humanized model offers new avenues for Parkinson's disease research and therapeutic development.
Area of Science:
- Neuroscience
- Immunology
- Stem Cell Biology
Background:
- Microglia, the brain immune cells, play a crucial role in neurodegenerative diseases like Parkinson's disease.
- Species-specific differences in microglia gene expression necessitate studying human microglia within a brain environment.
- The reactive nature of microglia requires models that accurately reflect human cellular responses.
Purpose of the Study:
- To establish a humanized mouse model for Parkinson's disease by transplanting human induced pluripotent stem cell-derived microglia.
- To investigate the behavior and function of human microglia in response to alpha-synuclein pathology in vivo.
- To assess the neuroprotective potential of human microglia in a Parkinson's disease model.
Main Methods:
- Transplantation of human induced pluripotent stem cell-derived hematopoietic progenitor cells into the striatum of immunodeficient mice.
- Intrastriatal injection of human alpha-synuclein preformed fibrils to induce Parkinson's disease pathology.
- Transcriptomic profiling and immunohistochemistry to analyze cellular responses and neuroprotection.
Main Results:
- Human cells successfully engrafted, matured into microglia, and maintained their phenotype for at least three months.
- Human microglia limited alpha-synuclein propagation and reduced local aggregates, offering mild protection to tyrosine hydroxylase neurons.
- Transcriptomic analysis revealed distinct gene expression changes in human microglia compared to host mouse cells, with hypocretin neuron preservation observed.
Conclusions:
- Human microglia exhibit neuroprotective functions in a Parkinson's disease model.
- The developed humanized mouse model is valuable for studying alpha-synuclein aggregation and testing therapeutic interventions.
- This model provides a more disease-relevant platform for Parkinson's disease research due to the use of human microglia.
