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A 3D human triculture system modeling neurodegeneration and neuroinflammation in Alzheimer’s disease
Open accessAbstract
Alzheimer's disease (AD) is characterized by beta-amyloid accumulation, phosphorylated tau formation, hyperactivation of glial cells, and neuronal loss. The mechanisms of AD pathogenesis, however, remain poorly understood, partially due to the lack of relevant models that can comprehensively recapitulate multistage intercellular interactions in human AD brains. Here we present a new three-dimensional (3D) human AD triculture model using neurons, astrocytes, and microglia in a 3D microfluidic platform. Our model provided key representative AD features: beta-amyloid aggregation, phosphorylated tau accumulation, and neuroinflammatory activity. In particular, the model mirrored microglial recruitment, neurotoxic activities such as axonal cleavage, and NO release damaging AD neurons and astrocytes. Our model will serve to facilitate the development of more precise human brain models for basic mechanistic studies in neural-glial interactions and drug discovery.
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“Improved models of AD are underway. These include the use of primates [276], brain organoids [249] and further transgenic mouse lines.”
From Microglia and monocytes in inflammatory CNS disease: integrating phenotype and function (2022) · cites this paper as [249]
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“This tri-culture system, consisting of human stem cell-derived neurons, astrocytes and microglia cultured within 3D Matrigel, was used to study the migration and phagocytosis of microglia as well as microglia-induced neurite degeneration and cell death in an AD brain-like environment.”
From Acoustofluidic assembly of 3D neurospheroids to model Alzheimer's disease (2020) · cites this paper as [23]
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“Several studies have demonstrated that astrocytes are capable of stimulating microglia phagocytosis by secretion of cytokines such as IL33 and the complement protein C3 [19, 34].”
From Crosstalk between astrocytes and microglia results in increased degradation of α-synuclein and amyloid-β aggregates (2021) · cites this paper as [34]
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“The model showed Aβ aggregation, p-tau accumulation, and secretion of inflammatory cytokines can be used to study the pathogenesis of AD.”
From Alzheimer's Disease: Treatment Strategies and Their Limitations. (2022) · cites this paper as [140]
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“Other than the neurotoxicity of Aβ aggregates, the AD brain contains more complex pathology, which is highly related to neuroinflammation.23, 43”
From Acoustofluidic assembly of 3D neurospheroids to model Alzheimer's disease (2020) · cites this paper as [23]
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“Recently, by integrating the microfluidics and 3D Matrigel matrix, a tri-culture model was established to recapitulate the key features of AD neuroinflammatory processes.23”
From Acoustofluidic assembly of 3D neurospheroids to model Alzheimer's disease (2020) · cites this paper as [23]
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Citations
Cites
2016 Alzheimer's disease facts and figures
Alzheimer's Association (2016) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2016.03.001 · Cited by 5,069
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Identification of a unique TGF-β–dependent molecular and functional signature in microglia
Butovsky, O., Jedrychowski, M. P., Moore, C. S., Cialic, R., Lanser, A. J., Gabriely, G., Koeglsperger, T., Dake, B., Wu, P. M., Doykan, C. E., et al. (2014) · Nature Neuroscience · doi:10.1038/nn.3599 · Cited by 2,543
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Probing sporadic and familial Alzheimer’s disease using induced pluripotent stem cells
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Self-citationAlzheimer’s Disease Risk Gene CD33 Inhibits Microglial Uptake of Amyloid Beta
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Additional file 1 of A 3D human co-culture to model neuron-astrocyte interactions in tauopathies
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Additional file 2 of A 3D human co-culture to model neuron-astrocyte interactions in tauopathies
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Metadata
- Authors
- Park, J., Wetzel, I., Marriott, I., Dréau, D., D’Avanzo, C., Kim, D. Y., Tanzi, R. E., & Cho, H.
- Affiliations
- University of North Carolina at Charlotte (US)
- Harvard University (US)
- Corresponding author
- Cho, Hansang
- ORCID
- Venue
- Nature Neuroscience
- Published
- 2018-06-27
- Volume
- 21
- Issue
- 7
- Pages
- 941-951
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- PMC
- PMC6800152
- OpenAlex
- W2809913775
- Cited by
- 644
- References
- 48
- Citations by year
- 2026: 35 · 2025: 78 · 2024: 90 · 2023: 91 · 2022: 78 · 2021: 110 · 2020: 92 · 2019: 58 · 2018: 12
- FWCI
- 46.76
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Aging (P01AG015379, R01AG061891, RF1AG048080, R01AG014713)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
- Keywords
- Alzheimer's disease, microfluidic platform, neuroinflammation, amyloid-beta aggregation, phosphorylated tau, microglial recruitment, human brain model
- MeSH terms
- Alzheimer Disease, Astrocytes, Humans, Inflammation, Nerve Degeneration, Neurons, Phosphorylation, Amyloid beta-Peptides, tau Proteins, Microglia, Cell Culture Techniques
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