APP antisense oligonucleotides are effective in rescuing mitochondrial phenotypes in human iPSC‐derived trisomy 21 astrocytes
Open accessAbstract
INTRODUCTION: Antisense oligonucleotides (ASOs) have shown promise in reducing amyloid precursor protein (APP) levels in neurons, but their effects in astrocytes, key contributors to neurodegenerative diseases, remain unclear. This study evaluates the efficacy of APP ASOs in astrocytes derived from an individual with Down syndrome (DS), a population at high risk for Alzheimer's disease (AD). METHODS: Human induced pluripotent stem cells (hiPSCs) from a healthy individual and an individual with DS were differentiated into astrocytes. Astrocytes were treated with APP ASOs for 10 days, and APP levels were quantified. Mitochondrial morphology and superoxide production in DS astrocytes were analyzed using super‐resolution and confocal microscopy. RESULTS: APP ASOs significantly reduced APP levels in astrocytes from both control and DS individuals. In DS astrocytes, treatment restored mitochondrial health, increasing mitochondrial number and size while reducing superoxide production. DISCUSSION: APP ASOs effectively reduce APP levels and improve mitochondrial health in astrocytes, suggesting their potential as a therapeutic approach for DS and DS‐related AD. Further in vivo studies are required to confirm these findings. Highlights: APP ASOs reduce APP levels in human iPSC‐derived astrocytes. APP ASO treatment rescues mitochondrial phenotypes in trisomy 21 astrocytes. This study supports ASOs as a potential therapy for Down syndrome‐related Alzheimer's disease.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
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?
A recent report in trisomy 21 iPSC-derived astrocytes showed upregulation of APP.
“consistent with a recent report in trisomy 21 iPSC-derived astrocytes that showed upregulation of APP [64].”
From Apolipoprotein E abundance is elevated in the brains of individuals with Down syndrome–Alzheimer’s disease (2025) · cites this paper as [64]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
How mitochondria produce reactive oxygen species
Murphy, M. P. (2009) · Biochemical Journal · doi:10.1042/bj20081386 · Cited by 8,207 · see citing works
Antonarakis, S. E., Skotko, B. G., Rafii, M. S., Strydom, A., Pape, S. E., Bianchi, D. W., Sherman, S. L., & Reeves, R. H. (2020) · Nature Reviews Disease Primers · doi:10.1038/s41572-019-0143-7 · Cited by 964 · see citing works
Antisense correction of SMN2 splicing in the CNS rescues necrosis in a type III SMA mouse modelPreprint
Hua, Y., Sahashi, K., Hung, G., Rigo, F., Passini, M. A., Bennett, C. F., & Krainer, A. R. (2010) · Genes & Development · doi:10.1101/gad.1941310 · Cited by 665 · see citing works
Therapeutic Antisense Oligonucleotides Are Coming of Age
Bennett, C. F. (2019) · Annual Review of Medicine · doi:10.1146/annurev-med-041217-010829 · Cited by 584 · see citing works
A genetic cause of Alzheimer disease: mechanistic insights from Down syndrome
Wiseman, F. K., Al-Janabi, T., Hardy, J., Karmiloff-Smith, A., Nizetic, D., Tybulewicz, V. L. J., Fisher, E. M. C., & Strydom, A. (2015) · Nature Reviews Neuroscience · doi:10.1038/nrn3983 · Cited by 562 · see citing works
Functional roles of reactive astrocytes in neuroinflammation and neurodegeneration
Patani, R., Hardingham, G. E., & Liddelow, S. A. (2023) · Nature Reviews Neurology · doi:10.1038/s41582-023-00822-1 · Cited by 531 · see citing works
Self-citationBusciglio, J., Pelsman, A., Wong, C., Pigino, G., Yuan, M., Mori, H., & Yankner, B. A. (2002) · Neuron · doi:10.1016/s0896-6273(02)00604-9 · Cited by 387 · see citing works
Down Syndrome, Partial Trisomy 21, and Absence of Alzheimer’s Disease: The Role of APP
Doran, E., Keator, D., Head, E., Phelan, M. J., Kim, R., Totoiu, M., Barrio, J. R., Small, G. W., Potkin, S. G., & Lott, I. T. (2017) · Journal of Alzheimer’s Disease · doi:10.3233/jad-160836 · Cited by 244 · see citing works
MitoSOX-Based Flow Cytometry for Detecting Mitochondrial ROS
Kauffman, M., Kauffman, M., Traore, K., Zhu, H., Trush, M. A., Jia, Z., & Li, Y. (2016) · doi:10.20455/ros.2016.865 · Cited by 233 · see citing works
Inflammatory processes induce beta-amyloid precursor protein changes in mouse brain.
Brugg, B., Lemaigre‐Dubreuil, Y., Huber, G., Wollman, E. E., Delhaye‐Bouchaud, N., & Mariani, J. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.7.3032 · Cited by 191 · see citing works
National population‐based estimates for major birth defects, 2016–2020
Stallings, E. B., Isenburg, J. L., Rutkowski, R. E., Kirby, R. S., Nembhard, W. N., Sandidge, T., Villavicencio, S., Nguyen, H. H., McMahon, D. M., Nestoridi, E., et al. (2024) · Birth Defects Research · doi:10.1002/bdr2.2301 · Cited by 165 · see citing works
Astrocyte calcium dysfunction causes early network hyperactivity in Alzheimer’s disease
Shah, D., Gsell, W., Wahis, J., Luckett, E. S., Jamoulle, T., Vermaercke, B., Preman, P., Moechars, D., Hendrickx, V., Jaspers, T., et al. (2022) · Cell Reports · doi:10.1016/j.celrep.2022.111280 · Cited by 153 · see citing works
Pathological phenotypes of astrocytes in Alzheimer’s disease
Kim, J., Yoo, I. D., Lim, J., & Moon, J. (2024) · Experimental & Molecular Medicine · doi:10.1038/s12276-023-01148-0 · Cited by 146 · see citing works
Hung, C., Tuck, E. J., Stubbs, V. E. L., van der Lee, S. J., Aalfs, C. M., van Spaendonk, R. M. L., Scheltens, P., Hardy, J., Holstege, H. H., & Livesey, F. J. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.109259 · Cited by 96 · see citing works
Self-citationTaha, D. M., Clarke, B. E., Hall, C. E., Tyzack, G. E., Ziff, O. J., Greensmith, L., Kalmár, B., Ahmed, M., Alam, A., Thelin, E. P., et al. (2021) · Brain · doi:10.1093/brain/awab328 · Cited by 48 · see citing works
Self-citationHung, C., Fertan, E., Livesey, F. J., Klenerman, D., & Patani, R. (2024) · Brain · doi:10.1093/brain/awae092 · Cited by 42 · see citing works
Self-citationAstrocytes in Down Syndrome Across the Lifespan
Ponroy Bally, B., & Murai, K. K. (2021) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2021.702685 · Cited by 35 · see citing works
Astroglial and microglial pathology in Down syndrome: Focus on Alzheimer's disease
Garcı́a, O., & Aguilar, L. F. (2022) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2022.987212 · Cited by 25 · see citing works
Importance of retrograde axonal transport in mitochondrial health and distribution
Hung, C. (2021) · Cell Death Discovery · doi:10.1038/s41420-021-00502-3 · Cited by 13 · see citing works
Self-citationAmyloid precursor protein induces reactive astrogliosis
Jáuregui, G. V., Vukić, D., Onyango, I. G., Arias, C., Novotný, J., Texlova, K., Wang, S., Kovačovicova, K. L., Polakova, N., Zelinková, J., et al. (2024) · Acta Physiologica · doi:10.1111/apha.14142 · Cited by 10 · see citing works
Thirumalai, S., Patani, R., & Hung, C. (2024) · Molecular Neurodegeneration · doi:10.1186/s13024-024-00745-5 · Cited by 10 · see citing works
Self-citation
Flagged first, then by citations
1 of the 22 references couldn’t be matched to a known paper.
Cited by
Sorted by citations
Farrell, C., Buhidma, Y., Mumford, P., Heywood, W. E., Hällqvist, J., Flores-Aguilar, L., Andrews, E. J., Rahimzadah, N., Taso, O. S., Doran, E., et al. (2025) · Acta Neuropathologica · doi:10.1007/s00401-025-02889-0 · Cited by 9 · see citing works
“2), consistent with a recent report in trisomy 21 iPSC-derived astrocytes that showed upregulation of APP [64].”
Mitochondrial Imbalance in Down Syndrome: A Driver of Accelerated Brain Aging?
Zuo, X. (2025) · Aging and Disease · doi:10.14336/ad.2025.0189 · Cited by 9 · see citing works
Development of Alzheimer’s disease in Down syndrome
García, O. A., Domínguez-de-la-Cruz, E., Luna-Martínez, I. G., Garnett-Carbajal, J. A., & Villegas-Piña, J. A. (2025) · Exploration of neuroscience · doi:10.37349/en.2025.1006104 · Cited by 4 · see citing works
Hung, C., Llorian, M., Pal, K., Livesey, F. J., Choudhary, J. S., Roumeliotis, T. I., & Patani, R. (2025) · Cell Reports · doi:10.1016/j.celrep.2025.115867 · Cited by 4 · see citing works
Self-citationSilva, A. L. T. E., de Oliveira, P. H. P., Yokota-Moreno, B. Y., Fausto, J. D. S., Avila, J. P., Nakaya, H. I., Sertie, A. L., & Zampieri, B. L. (2025) · Acta Neuropathologica Communications · doi:10.1186/s40478-025-02090-0 · Cited by 5 · see citing works
A Change of Mind: Targeting Amyloid-β with Better Safety Profile
Krick, K. E., & Wilcock, D. M. (2025) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-062124-113434 · Cited by 1 · see citing works
Casals-Sendra, G., Jarne-Sanz, I., Catasús, N., Boluda-Luis, I., Quer, A., Amilibia, E., Lázaro, C., Serra, E., Blanco, I., & Castellanos, E. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.11.14.688164
Casals-Sendra, G., Jarne-Sanz, I., Catasús, N., Boluda-Luis, I., Quer, A., Amilibia, E., Plotkin, S. R., Lázaro, C., Serra, E., Blanco, I., et al. (2026) · Molecular Therapy — Nucleic Acids · doi:10.1016/j.omtn.2026.103046
- Authors
- Thirumalai, S., Livesey, F. J., Patani, R., & Hung, C.
- Affiliations
- University College London (GB)
- The Francis Crick Institute (GB)
- City University of Hong Kong (HK)
- Corresponding author
- Patani, Rickie
- Hung, Christy
- Venue
- Alzheimer's & Dementia
- Publisher
- Wiley
- Published
- 2025-01
- Volume
- 21
- Issue
- 1
- Pages
- e14560-e14560
- ISSN
- 1552-5260 (ISSN-L)
- 1552-5279
- PMC
- PMC11775556
- OpenAlex
- W4406933136
- Cited by
- 9
- References
- 22
- Citations by year
- 2026: 1 · 2025: 8
- FWCI
- 5.75
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Alzheimer s & Dementia (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion, cc-by)
- Figshare (submittedVersion, cc-by)
- CityU Scholars (submittedVersion, cc-by)
- The Francis Crick Institute (cc-by)
- Funders
- Alzheimer’s Research UK
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Down syndrome and intellectual disability research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Keywords
- antisense oligonucleotides, amyloid precursor protein
- MeSH terms
- Astrocytes, Cells, Cultured, Down Syndrome, Humans, Mitochondria, Phenotype, Oligonucleotides, Antisense, Amyloid beta-Protein Precursor, Induced Pluripotent Stem Cells
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
