The DOI matches its Crossref record; 61 of the 61 references it cites were found in a registry or an index.
Infiltrating CD8+ T cells exacerbate Alzheimer’s disease pathology in a 3D human neuroimmune axis model
Open accessAbstract
Brain infiltration of peripheral immune cells and their interactions with brain-resident cells may contribute to Alzheimer's disease (AD) pathology. To examine these interactions, in the present study we developed a three-dimensional human neuroimmune axis model comprising stem cell-derived neurons, astrocytes and microglia, together with peripheral immune cells. We observed an increase in the number of T cells (but not B cells) and monocytes selectively infiltrating into AD relative to control cultures. Infiltration of CD8+ T cells into AD cultures led to increased microglial activation, neuroinflammation and neurodegeneration. Using single-cell RNA-sequencing, we identified that infiltration of T cells into AD cultures led to induction of interferon-γ and neuroinflammatory pathways in glial cells. We found key roles for the C-X-C motif chemokine ligand 10 (CXCL10) and its receptor, CXCR3, in regulating T cell infiltration and neuronal damage in AD cultures. This human neuroimmune axis model is a useful tool to study the effects of peripheral immune cells in brain disease.
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“The study found that C-X-C motif chemokine ligand 10 (CXCL10) and its receptor CXCR3 play key roles in regulating the infiltration of CD8+ T cells into the brain, and the infiltrated CD8+ T cells appear to interact with microglia to jointly promote AD’s neurodegeneration.257”
From Recent advances in Alzheimer's disease: Mechanisms, clinical trials and new drug development strategies. (2024) · cites this paper as [257]
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“T-lymphocyte infiltration into the brain has been previously reported in AD patients and has been associated with impaired cognition (Gate et al., 2020; Jorfi et al., 2023).”
From Cholesterol 25-hydroxylase mediates neuroinflammation and neurodegeneration in a mouse model of tauopathy (2024) · cites this paper as Jorfi et al., 2023
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“Although B cells infiltrated the in vitro 3D model of AD brain in very low numbers, they significantly elevated protein levels of complement proteins and chemokines compared to cultures lacking B cells [83].”
From Is there a role for B cells in Alzheimer's disease? (2026) · cites this paper as [83]
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“The results revealed that B cells do not preferentially infiltrate AD 3D cultures compared to control cultures. Instead, B cell infiltration was significantly reduced, particularly in the presence of microglia [83].”
From Is there a role for B cells in Alzheimer's disease? (2026) · cites this paper as [83]
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Cites
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A three-dimensional human neural cell culture model of Alzheimer’s disease
Choi, S. H., Kim, Y. H., Hebisch, M., Sliwinski, C., Lee, S., D’Avanzo, C., Chen, H., Hooli, B., Asselin, C., Muffat, J., et al. (2014) · Nature · doi:10.1038/nature13800 · Cited by 1,195
Self-citationiPSC-derived human microglia-like cells to study neurological diseases
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Clonally expanded CD8 T cells patrol the cerebrospinal fluid in Alzheimer’s disease
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Cited by
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Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases
Loh, J. S., Mak, W. Q., Tan, L. K. S., Ng, C. X., Chan, H. H., Yeow, S. H., Foo, J. B., Ong, Y. S., How, C. W., & Khaw, K. Y. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-01743-1 · Cited by 1,193
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Neuroinflammation in Alzheimer disease
Heneka, M. T., van der Flier, W. M., Jessen, F., Hoozemanns, J., Thal, D. R., Boche, D., Brosseron, F., Teunissen, C., Zetterberg, H., Jacobs, A. H., et al. (2025) · Nature Reviews Immunology · doi:10.1038/s41577-024-01104-7 · Cited by 638
Inflammatory aspects of Alzheimer’s disease
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Peripheral and central neuroimmune mechanisms in Alzheimer’s disease pathogenesis
Zhang, S., Gao, Y., Zhao, Y., Huang, T. Y., Zheng, Q., & Wang, X. (2025) · Molecular Neurodegeneration · doi:10.1186/s13024-025-00812-5 · Cited by 78
Metadata
- Authors
- Jorfi, M., Park, J., Hall, C. K., Lin, C.-C. J., Chen, M., von Maydell, D., Kruskop, J. M., Kang, B., Choi, Y., Prokopenko, D., Irimia, D., Kim, D. Y., & Tanzi, R. E.
- Affiliations
- Harvard University (US)
- Massachusetts General Hospital (US)
- Corresponding author
- Jorfi, Mehdi
- Kim, Doo Yeon
- Tanzi, Rudolph E.
- ORCID
- Venue
- Nature Neuroscience
- Published
- 2023-08-24
- Volume
- 26
- Issue
- 9
- Pages
- 1489-1504
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- PMC
- PMC11184920
- OpenAlex
- W4386134158
- Cited by
- 214
- References
- 61
- Citations by year
- 2026: 68 · 2025: 65 · 2024: 74 · 2023: 7
- FWCI
- 22.37
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Cure Alzheimer’s Fund
- JPB Foundation
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
- Keywords
- Alzheimer's disease, CD8+ T cells, T cell infiltration, neuroinflammation, microglial activation, neurodegeneration, CXCL10, CXCR3, interferon-gamma, peripheral immune cells, stem cell-derived neurons, astrocytes, monocytes
- MeSH terms
- Alzheimer Disease, Humans, Neuroglia, Neurons, Neuroimmunomodulation, CD8-Positive T-Lymphocytes
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