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Cited by 31Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

Cerebral organoids with chromosome 21 trisomy secrete Alzheimer’s disease-related soluble aggregates detectable by single-molecule-fluorescence and super-resolution microscopy

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Fertan, Emre, Böken, Dorothea, Murray, Aoife, Danial, John S. H., Lam, Jeff Y. L., Wu, Yunzhao, Goh, Pollyanna A., Alić, Ivan +5 more·2024·Molecular Psychiatry
DOI 10.1038/s41380-023-02333-3PMC PMC11116105
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Abstract

Understanding the role of small, soluble aggregates of beta-amyloid (Aβ) and tau in Alzheimer’s disease (AD) is of great importance for the rational design of preventative therapies. Here we report a set of methods for the detection, quantification, and characterisation of soluble aggregates in conditioned media of cerebral organoids derived from human iPSCs with trisomy 21, thus containing an extra copy of the amyloid precursor protein (APP) gene. We detected soluble beta-amyloid (Aβ) and tau aggregates secreted by cerebral organoids from both control and the isogenic trisomy 21 (T21) genotype. We developed a novel method to normalise measurements to the number of live neurons within organoid-conditioned media based on glucose consumption. Thus normalised, T21 organoids produced 2.5-fold more Aβ aggregates with a higher proportion of larger (300–2000 nm 2) and more fibrillary-shaped aggregates than controls, along with 1.3-fold more soluble phosphorylated tau (pTau) aggregates, increased inflammasome ASC-specks, and a higher level of oxidative stress inducing thioredoxin-interacting protein (TXNIP). Importantly, all this was detectable prior to the appearance of histological amyloid plaques or intraneuronal tau-pathology in organoid slices, demonstrating the feasibility to model the initial pathogenic mechanisms for AD in-vitro using cells from live genetically pre-disposed donors before the onset of clinical disease. Then, using different iPSC clones generated from the same donor at different times in two independent experiments, we tested the reproducibility of findings in organoids. While there were differences in rates of disease progression between the experiments, the disease mechanisms were conserved. Overall, our results show that it is possible to non-invasively follow the development of pathology in organoid models of AD over time, by monitoring changes in the aggregates and proteins in the conditioned media, and open possibilities to study the time-course of the key pathogenic processes taking place.

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Cited by

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Authors
Fertan, E., Böken, D., Murray, A., Danial, J. S. H., Lam, J. Y. L., Wu, Y., Goh, P. A., Alić, I., Cheetham, M. R., Lobanova, E., Zhang, Y. P., Nižetić, D., & Klenerman, D.
Affiliations
  • University of Cambridge (GB)
  • Queen Mary University of London (GB)
Corresponding author
Klenerman, David
ORCID
Venue
Molecular Psychiatry
Publisher
Springer Science and Business Media LLC
Published
2023-12-15
Volume
29
Issue
2
Pages
369-386
ISSN
  • 1359-4184 (ISSN-L)
  • 1476-5578
DOI
10.1038/s41380-023-02333-3
PMC
PMC11116105
OpenAlex
W4389816879
Cited by
31
References
16
Citations by year
2026: 9 · 2025: 13 · 2024: 9
FWCI
5.51
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Psychiatry (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Apollo (University of Cambridge) (submittedVersion, cc-by)
  • DR-NTU (Nanyang Technological University) (submittedVersion)
  • Queen Mary Research Online (Queen Mary University of London) (submittedVersion, cc-by)
  • Apollo (cc-by)
Funders
  • Wellcome Trust (608765, 217199/Z/19/Z)
  • European Commission (608765)
  • Fondation Jérôme Lejeune
  • Croucher Foundation
  • UK Dementia Research Institute
  • Medical Research Council (608765)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
Alzheimer's disease, brain organoids, Down syndrome, amyloid-beta aggregates, tau phosphorylation, amyloid precursor protein, iPSC-derived neurons, conditioned medium, TXNIP, oxidative stress, in vitro disease model, single-molecule fluorescence, super-resolution microscopy
MeSH terms
Alzheimer Disease, Brain, Carrier Proteins, Down Syndrome, Humans, Microscopy, Fluorescence, Neurons, Organoids, Trisomy, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, tau Proteins, Culture Media, Conditioned, Oxidative Stress, Induced Pluripotent Stem Cells, Plaque, Amyloid

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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 ›

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