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Published on: July 6, 2019
Advanced patient-specific microglia cell models for pre-clinical studies in Alzheimer's disease
Carla Cuní-López1,2, Romal Stewart1,3, Lotta E Oikari1,4
1Mental Health and Neuroscience Department, QIMR Berghofer Medical Research Institute, Herston, QLD, 4006, Australia.
Background:
Alzheimer's disease (AD) is an incurable neurodegenerative disorder with a rapidly increasing prevalence worldwide. Current approaches targeting hallmark pathological features of AD have had no consistent clinical benefit. Neuroinflammation is a major contributor to neurodegeneration and hence, microglia, the brain's resident immune cells, are an attractive target for potentially more effective therapeutic strategies. However, there is no current in vitro model system that captures AD patient-specific microglial characteristics using physiologically relevant and experimentally flexible culture conditions.
Methods:
To address this shortcoming, we developed novel 3D Matrigel-based monocyte-derived microglia-like cell (MDMi) mono-cultures and co-cultures with neuro-glial cells (ReNcell VM). We used single-cell RNA sequencing (scRNAseq) analysis to compare the transcriptomic signatures of MDMi between model systems (2D, 3D and 3D co-culture) and against published human microglia datasets. To demonstrate the potential of MDMi for use in personalized pre-clinical strategies, we generated and characterized MDMi models from sixteen AD patients and matched healthy controls, and profiled cytokine responses upon treatment with anti-inflammatory drugs (dasatinib and spiperone).
Results:
MDMi in 3D exhibited a more branched morphology and longer survival in culture compared to 2D. scRNAseq uncovered distinct MDMi subpopulations that exhibit higher functional heterogeneity and best resemble human microglia in 3D co-culture. AD MDMi in 3D co-culture showed altered cell-to-cell interactions, growth factor and cytokine secretion profiles and responses to amyloid-β. Drug testing assays revealed patient- and model-specific cytokine responses.
Conclusion:
Our study presents a novel, physiologically relevant and AD patient-specific 3D microglia cell model that opens avenues towards improving personalized drug development strategies in AD.
Insights
A new 3D cell model using microglia-like cells (MDMi) from Alzheimer's disease (AD) patients offers a more accurate way to study the disease and develop personalized treatments.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Alzheimer's disease (AD) is a progressive neurodegenerative disorder with increasing global prevalence.
- Current AD therapies lack consistent clinical efficacy, highlighting the need for novel therapeutic targets.
- Neuroinflammation, driven by microglia, is a key factor in AD pathogenesis, making microglia a promising therapeutic target.
Purpose of the Study:
- To develop a physiologically relevant in vitro model system for studying Alzheimer's disease (AD) patient-specific microglia.
- To create a flexible cell culture system that captures AD patient-specific microglial characteristics.
- To establish a platform for personalized pre-clinical drug development strategies in AD.
Main Methods:
- Developed novel 3D Matrigel-based monocyte-derived microglia-like cell (MDMi) mono- and co-cultures.
- Utilized single-cell RNA sequencing (scRNAseq) to compare transcriptomic signatures of MDMi across different model systems (2D, 3D, 3D co-culture) and against human microglia datasets.
- Generated and characterized MDMi models from sixteen AD patients and matched healthy controls, profiling cytokine responses to anti-inflammatory drugs.
Main Results:
- 3D MDMi cultures exhibited enhanced branched morphology and extended survival compared to 2D cultures.
- scRNAseq revealed distinct MDMi subpopulations in 3D co-culture that closely resemble human microglia, displaying higher functional heterogeneity.
- AD MDMi in 3D co-culture demonstrated altered cell-cell interactions, cytokine secretion profiles, and responses to amyloid-beta, with patient- and model-specific drug responses observed.
Conclusions:
- A novel, physiologically relevant, and AD patient-specific 3D microglia cell model was developed.
- This 3D MDMi model provides a valuable platform for advancing personalized drug development strategies for Alzheimer's disease.
- The model's ability to capture patient-specific characteristics opens new avenues for targeted therapeutic interventions in AD.
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