Secretome from SH-SY5Y APPSwe cells trigger time-dependent CHME3 microglia activation phenotypes, ultimately leading to miR-21 exosome shuttling
Open accessAbstract
Exosome-mediated intercellular communication has been increasingly recognized as having a broad impact on Alzheimer's disease (AD) pathogenesis. Still, limited information exists regarding their "modus operandi", as it critically depends on exosomal cargo, environmental context and target cells. Therefore, a more thorough understanding of the role of exosomes from different cell types as mediators of neuroinflammation in AD context is a decisive step to open avenues for innovative and efficient therapies. In this study, we demonstrate that SH-SY5Y cells transfected with the Swedish mutant of APP 695 (SH Swe ) remarkably express increased inflammatory markers, combined with higher APP and Aβ 1-40 production, when compared to naïve SH-SY5Y (SH) cells. Although exerting an early clearance effect on extracellular APP and Aβ accumulation when in co-culture with SH Swe cells, human CHME3 microglia gradually lose such property, and express both pro-inflammatory (iNOS, IL-1β, TNF-α, MHC class II, IL-6) and pro-resolving genes (IL-10 and Arginase 1), while also evidence increased senescence-associated β-galactosidase activity. Interestingly, upregulation of inflammatory-associated miRNA (miR)-155, miR-146a and miR-124 by SH Swe secretome shows to be time-dependent and to inversely correlate with their respective targets (SOCS-1, IRAK1 and C/EBP-α). We report that microglia also internalize exosomes released from SH Swe cells, which are enriched in miR-155, miR-146a, miR-124, miR-21 an…
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
miRNAs can be released by cells as free species directly into their secretome or selectively enriched in exosomes (diameter <150 nm) that, when internalized by target cells, affect their biological functions.
“In general, miRNAs can be released by cells as free species directly into their secretome or selectively enriched in small extracellular vesicles (exosomes, diameter size <150 nm) that, when internalized by target cells, affect their biological functions [38,39,40,41].”
From Emerging Role of miR-21-5p in Neuron–Glia Dysregulation and Exosome Transfer Using Multiple Models of Alzheimer’s Disease (2022) · cites this paper as [39]
Elevation of miR-21 leads to microglial pro-inflammatory polarization in diverse pathological contexts.
“the elevation of miR-21 led to microglial pro-inflammatory polarization in diverse pathological contexts [39,60,61,62].”
From Emerging Role of miR-21-5p in Neuron–Glia Dysregulation and Exosome Transfer Using Multiple Models of Alzheimer’s Disease (2022) · cites this paper as [39]
miR-21 is upregulated in SWE cells and in iPSC-derived neurons from patients with the PSEN1 mutation.
“Our previously published data have shown the upregulation of miR-21 in SWE cells and in iPSC-derived neurons from patients with the PSEN1 mutation [25,39,40].”
From Emerging Role of miR-21-5p in Neuron–Glia Dysregulation and Exosome Transfer Using Multiple Models of Alzheimer’s Disease (2022) · cites this paper as [39]
Exosomal miRNA cargo may depend on intracellular miRNA levels and active/passive transference.
“We have previously shown that exosomal miRNA cargo may depend on intracellular miRNA levels and active/passive transference [39,61,62].”
From Emerging Role of miR-21-5p in Neuron–Glia Dysregulation and Exosome Transfer Using Multiple Models of Alzheimer’s Disease (2022) · cites this paper as [39]
Increased miR-21 in SWE cells is secreted into exosomes, leading to CHME3 microglial miR-21 overexpression and inclusion in their derived exosomes.
“Our previous study using human SH/SWE neuroblastoma cells and CHME3 microglia cocultures revealed that increased miR-21 in SWE cells was secreted into their exosomes, which led to CHME3 microglial miR-21 overexpression and its inclusion in their derived exosomes [39].”
From Emerging Role of miR-21-5p in Neuron–Glia Dysregulation and Exosome Transfer Using Multiple Models of Alzheimer’s Disease (2022) · cites this paper as [39]
SWE cell transplantation caused increased hippocampal microglial activation compared with non-transplanted or SH engraftment.
“Here, we observed the efficient transplantation of SWE cells, which caused increased hippocampal microglial activation when compared to non-transplanted or SH engraftment, further confirming our previous studies centered on the paracrine influence of SWE cells on microglial activation [39,40].”
From Emerging Role of miR-21-5p in Neuron–Glia Dysregulation and Exosome Transfer Using Multiple Models of Alzheimer’s Disease (2022) · cites this paper as [39]
Neu-AD cells showed upregulated miR-21, miR-124 and miR-125b.
“However, Neu-AD showed upregulated miR-21, miR-124 and miR-125b, which are all found to be dysregulated in AD models [25,39,76].”
From Emerging Role of miR-21-5p in Neuron–Glia Dysregulation and Exosome Transfer Using Multiple Models of Alzheimer’s Disease (2022) · cites this paper as [39]
miR-21 overexpression in MG-AD mirrored previous findings in the CHME3 microglial cell line exposed to SWE-derived exosomes.
“Note that miR-21 overexpression mirrored what we have previously reported in the CHME3 microglial cell line exposed to SWE-derived exosomes [39].”
From Emerging Role of miR-21-5p in Neuron–Glia Dysregulation and Exosome Transfer Using Multiple Models of Alzheimer’s Disease (2022) · cites this paper as [39]
Cites
Immune attack: the role of inflammation in Alzheimer disease
Heppner, F. L., Ransohoff, R. M., & Becher, B. (2015) · Nature Reviews Neuroscience · doi:10.1038/nrn3880 · Cited by 2,134 · see citing works
Citron, M., Oltersdorf, T., Haass, C., McConlogue, L., Hung, A. Y., Seubert, P., Vigo-Pelfrey, C., Lieberburg, I., & Selkoe, D. J. (1992) · Nature · doi:10.1038/360672a0 · Cited by 1,757 · see citing works
Microglial Dysfunction and Defective β-Amyloid Clearance Pathways in Aging Alzheimer's Disease Mice
Hickman, S. E., Allison, E. K., & El Khoury, J. (2008) · The Journal of Neuroscience · doi:10.1523/jneurosci.0616-08.2008 · Cited by 1,329 · see citing works
Microglia in Alzheimer's disease
Sarlus, H., & Heneka, M. T. (2017) · Journal of Clinical Investigation · doi:10.1172/jci90606 · Cited by 911 · see citing works
Brites, D., & Fernandes, A. (2015) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2015.00476 · Cited by 599 · see citing works
Self-citationCheung, Y.-T., Lau, W. K.-W., Yu, M.-S., Lai, C. S.-W., Yeung, S.-C., So, K.-F., & Chang, R. C.-C. (2009) · NeuroToxicology · doi:10.1016/j.neuro.2008.11.001 · Cited by 576 · see citing works
Mechanisms of Aβ Clearance and Degradation by Glial Cells
Ries, M., & Sastre, M. (2016) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2016.00160 · Cited by 527 · see citing works
Cardoso, A. L., Guedes, J. R., Pereira de Almeida, L., & Pedroso de Lima, M. C. (2012) · Immunology · doi:10.1111/j.1365-2567.2011.03514.x · Cited by 336 · see citing works
Arginase 1+ microglia reduce Aβ plaque deposition during IL-1β-dependent neuroinflammation
Cherry, J. D., Olschowka, J. A., & O’Banion, M. K. (2015) · Journal of Neuroinflammation · doi:10.1186/s12974-015-0411-8 · Cited by 152 · see citing works
Harrison, E. B., Hochfelder, C. G., Lamberty, B. G., Meays, B. M., Morsey, B. M., Kelso, M. L., Fox, H. S., & Yelamanchili, S. V. (2016) · FEBS Open Bio · doi:10.1002/2211-5463.12092 · Cited by 151 · see citing works
Femminella, G. D., Ninan, S., Atkinson, R., Fan, Z., Brooks, D. J., & Edison, P. (2016) · Journal of Alzheimer’s Disease · doi:10.3233/jad-150827 · Cited by 88 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Therapeutically harnessing extracellular vesicles
Cheng, L., & Hill, A. F. (2022) · Nature Reviews Drug Discovery · doi:10.1038/s41573-022-00410-w · Cited by 737 · see citing works
Garcia, G., Pinto, S., Ferreira, S., Lopes, D., Serrador, M. J., Fernandes, A., Vaz, A. R., Mendonça, A. D., Edenhofer, F., Malm, T., et al. (2022) · Cells · doi:10.3390/cells11213377 · Cited by 55 · see citing works
“Our previous studies showed that miR-124, miR-125b, miR-21, miR-146a and miR-155 were upregulated in SWE cells, together with higher APP and Aβ production, when compared to SH cells, and that miR-124 drove microglia polarization [25,39,40].”
BackgroundMethodResultInfluentialSelf-citationVaz, A. R., Pinto, S., Ezequiel, C., Cunha, C., Carvalho, L. A., Moreira, R., & Brites, D. (2019) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2019.00109 · Cited by 55 · see citing works
Self-citationRole of Glia-Derived Extracellular Vesicles in Neurodegenerative Diseases
Li, T., Tan, X., Li, S., Al-Nusaif, M., & Le, W. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.765395 · Cited by 33 · see citing works
- Authors
- Fernandes, A., Ribeiro, A. R., Monteiro, M., Garcia, G., Vaz, A. R., & Brites, D.
- Affiliations
- University of Lisbon (PT)
- Corresponding author
- Brites, Dora
- Venue
- Biochimie
- Publisher
- Elsevier BV
- Published
- 2018-12
- Volume
- 155
- Pages
- 67-82
- ISSN
- 0037-9042 (ISSN-L)
- 0300-9084
- OpenAlex
- W2805889137
- Cited by
- 93
- References
- 11
- Citations by year
- 2026: 10 · 2025: 7 · 2024: 7 · 2023: 11 · 2022: 17 · 2021: 25 · 2020: 9 · 2019: 5 · 2018: 2
- FWCI
- 4.62
- Type
- journal article
- Language
- en
- Open access
- green
- zenodo.org
- Licence
- Locations
- Biochimie (publishedVersion)
- PubMed (publishedVersion)
- Zenodo (CERN European Organization for Nuclear Research) (submittedVersion, other-oa)
- Funders
- EU Joint Programme – Neurodegenerative Disease Research
- Fundação para a Ciência e a Tecnologia (FCT-EXPL/NEU-NMC/1003/2013, JPco-fuND /0003/2015, SFRH/BD/128738/2017, SFRH/BPD/76590/2011, UID/DTP/04138/2013)
- Horizon 2020 (643417)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
- Keywords
- Alzheimer's disease, exosomes, microglial activation, secretome, SH-SY5Y cells, amyloid-beta, neuroinflammation, neuron-microglia communication, miR-21, exosomal microRNAs, miR-155, miR-146a, miR-124, miR-125b, S100B, HMGB1, exosome internalization, neuroprotection
- MeSH terms
- Alzheimer Disease, Cell Communication, Humans, Neurons, Cytokines, Amyloid beta-Protein Precursor, Microglia, MicroRNAs, Cell Line, Tumor, Exosomes
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
