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Fabrication of Amyloid-β-Secreting Alginate Microbeads for Use in Modelling Alzheimer's Disease
Published on: July 6, 2019
A neuroimmune cerebral assembloid model to study the pathophysiology of familial Alzheimer's disease
Andrea Becerra-Calixto1, Anik Banerjee1, Huihui Fan1
1Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA.
Abstract:
Alzheimer's disease (AD) is the leading cause of dementia globally. The accumulation of amyloid and tau proteins, neuronal cell death and neuroinflammation are seen with AD progression, resulting in memory and cognitive impairment. Microglia are crucial for AD progression as they engage with neural cells and protein aggregates to regulate amyloid pathology and neuroinflammation. Recent studies indicate that microglia contribute to the propagation of amyloid beta (Aβ) via their immunomodulatory functions including Aβ phagocytosis and inflammatory cytokine production. Three-dimensional cell culture techniques provide the opportunity to study pathophysiological changes in AD in human-derived samples that are difficult to recapitulate in animal models (e.g., transgenic mice). However, these models often lack immune cells such as microglia, which play a critical role in AD pathophysiology. In this study, we developed a neuroimmune assembloid model by integrating cerebral organoids (COs) with induced microglia-like cells (iMGs) derived from human induced pluripotent stem cells from familial AD patient with PSEN2 mutation. After 120 days in culture, we found that iMGs were successfully integrated within the COs. Interestingly, our assembloids displayed histological, functional and transcriptional features of the pro-inflammatory environment seen in AD, including amyloid plaque-like and neurofibrillary tangle-like structures, reduced microglial phagocytic capability, and enhanced neuroinflammatory and apoptotic gene expression. In conclusion, our neuroimmune assembloid model effectively replicates the inflammatory phenotype and amyloid pathology seen in AD.
Insights
Researchers developed a novel neuroimmune assembloid model using human cells to study Alzheimer's disease (AD). This model successfully replicates key AD pathologies, including amyloid plaques and neuroinflammation, offering new insights into disease mechanisms.
Area of Science:
- Neuroscience
- Immunology
- Stem Cell Biology
Background:
- Alzheimer's disease (AD) is a leading cause of dementia, characterized by amyloid and tau protein accumulation, neuroinflammation, and neuronal death.
- Microglia play a critical role in AD pathogenesis, influencing amyloid pathology and neuroinflammation through phagocytosis and cytokine production.
- Existing 3D cell culture models often lack microglia, limiting their ability to fully recapitulate AD pathophysiology.
Purpose of the Study:
- To develop a novel neuroimmune assembloid model integrating human cerebral organoids (COs) with induced microglia-like cells (iMGs).
- To investigate the utility of this model in replicating the inflammatory and pathological features of Alzheimer's disease.
Main Methods:
- Developed a neuroimmune assembloid by co-culturing cerebral organoids (COs) with induced microglia-like cells (iMGs) derived from familial AD patient iPSCs (PSEN2 mutation).
- Cultured the assembloids for 120 days to allow for cell integration and disease modeling.
- Analyzed histological, functional, and transcriptional features to assess AD-like pathology and neuroinflammation.
Main Results:
- Successfully integrated iMGs within the cerebral organoids after 120 days of culture.
- Observed histological features resembling amyloid plaques and neurofibrillary tangles.
- Demonstrated a pro-inflammatory environment with reduced microglial phagocytic capability and enhanced neuroinflammatory and apoptotic gene expression.
Conclusions:
- The developed neuroimmune assembloid model effectively replicates the inflammatory phenotype and amyloid pathology characteristic of Alzheimer's disease.
- This human-derived 3D model provides a valuable platform for studying AD pathophysiology, particularly the role of microglia.
- The model's ability to recapitulate key AD features offers potential for future drug screening and therapeutic development.
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