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Patient-specific Alzheimer-like pathology in trisomy 21 cerebral organoids reveals BACE2 as a gene dose-sensitive AD suppressor in human brain
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Abstract
A population of more than six million people worldwide at high risk of Alzheimer’s disease (AD) are those with Down Syndrome (DS, caused by trisomy 21 (T21)), 70% of whom develop dementia during lifetime, caused by an extra copy of β-amyloid-(Aβ)-precursor-protein gene. We report AD-like pathology in cerebral organoids grown in vitro from non-invasively sampled strands of hair from 71% of DS donors. The pathology consisted of extracellular diffuse and fibrillar Aβ deposits, hyperphosphorylated/pathologically conformed Tau, and premature neuronal loss. Presence/absence of AD-like pathology was donor-specific (reproducible between individual organoids/iPSC lines/experiments). Pathology could be triggered in pathology-negative T21 organoids by CRISPR/Cas9-mediated elimination of the third copy of chromosome 21 gene BACE2 , but prevented by combined chemical β and γ-secretase inhibition. We found that T21 organoids secrete increased proportions of Aβ-preventing (Aβ1–19) and Aβ-degradation products (Aβ1–20 and Aβ1–34). We show these profiles mirror in cerebrospinal fluid of people with DS. We demonstrate that this protective mechanism is mediated by BACE2 -trisomy and cross-inhibited by clinically trialled BACE1 inhibitors. Combined, our data prove the physiological role of BACE2 as a dose-sensitive AD-suppressor gene, potentially explaining the dementia delay in ~30% of people with DS. We also show that DS cerebral organoids could be explored as pre-morbid AD-risk population detector and a system for hypothesis-free drug screens as well as identification of natural suppressor genes for neurodegenerative diseases.
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“Evidence in preclinical models demonstrates that genes other than APP being in three copies modify aspects of DSAD, such as cognition and amyloid-β load [1, 50, 70]”
From Apolipoprotein E abundance is elevated in the brains of individuals with Down syndrome–Alzheimer’s disease (2025) · cites this paper as [1]
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Self-citationSynaptic and intrinsic membrane defects disrupt early neural network dynamics in Down syndrome
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It’s good to know what to BACE the specificity of your inhibitors on
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Metadata
- Authors
- Alić, I., Goh, P. A., Murray, A., Portelius, E., Gkanatsiou, E., Gough, G., Mok, K. Y., Koschut, D., Brunmeir, R., Yeap, Y. J., O’Brien, N. L., Groet, J., Shao, X., Havlicek, S., Dunn, N. R., Kvartsberg, H., Brinkmalm, G., Hithersay, R., Startin, C., Hamburg, S., Phillips, M., Pervushin, K., Turmaine, M., Wallon, D., Rovelet-Lecrux, A., Soininen, H., Volpi, E., Martin, J. E., Foo, J. N., Becker, D. L., Rostagno, A., Ghiso, J., Krsnik, Ž., Šimić, G., Kostović, I., Mitrečić, D., LonDownS Consortium, Strydom, A., Fisher, E., Wiseman, F., Nizetic, D., Hardy, J., Tybulewicz, V., Karmiloff-Smith, A., Francis, P. T., Blennow, K., Strydom, A., Hardy, J., Zetterberg, H., & Nižetić, D.
- Affiliations
- Queen Mary University of London (GB)
- Nanyang Technological University (SG)
- University of Gothenburg (SE)
- UCL Queen Square Institute of Neurology (GB)
- Agency for Science, Technology and Research (SG)
- King's College London (GB)
- University College London (GB)
- Inserm (FR)
- University of Eastern Finland (FI)
- University of Westminster (GB)
- New York University (US)
- University of Zagreb (HR)
- The Francis Crick Institute (GB)
- ORCID
- Alić, Ivan
- Goh, Pollyanna A.
- Murray, Aoife
- Portelius, Erik
- Gkanatsiou, Eleni
- Gough, Gillian
- Mok, Kin Y.
- Koschut, David
- Brunmeir, Reinhard
- Yeap, Yee Jie
- O’Brien, Niamh L.
- Shao, Xiaowei
- Dunn, N. Ray
- Kvartsberg, Hlin
- Brinkmalm, Gunnar
- Hithersay, Rosalyn
- Startin, Carla
- Hamburg, Sarah
- Pervushin, Konstantin
- Wallon, David
- Soininen, Hilkka
- Volpi, Emanuela
- Martin, Joanne E.
- Foo, Jia Nee
- Becker, David L.
- Rostagno, Agueda
- Ghiso, Jorge
- Krsnik, Željka
- Šimić, Goran
- Kostović, Ivica
- Mitrečić, Dinko
- Fisher, Elizabeth
- Wiseman, Frances
- Tybulewicz, Victor
- Francis, Paul T.
- Blennow, Kaj
- Zetterberg, Henrik
- Nižetić, Dean
- Venue
- Molecular Psychiatry
- Published
- 2020-07-10
- Volume
- 26
- Issue
- 10
- Pages
- 5766-5788
- ISSN
- 1359-4184 (ISSN-L)
- 1476-5578
- PMC
- PMC8190957
- OpenAlex
- W3041871366
- Cited by
- 123
- References
- 64
- Citations by year
- 2026: 9 · 2025: 22 · 2024: 16 · 2023: 21 · 2022: 20 · 2021: 24 · 2020: 9
- FWCI
- 11.73
- Type
- journal article
- Language
- en
- Update notices
- correction (2021-07-16)
- Open access
- hybrid
- doi.org
- Locations
- Molecular Psychiatry (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed Central (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- DR-NTU (Nanyang Technological University) (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- Research Portal (King's College London) (submittedVersion, cc-by)
- Queen Mary Research Online (Queen Mary University of London) (submittedVersion, cc-by)
- WestminsterResearch (University of Westminster) (submittedVersion, cc-by)
- The Francis Crick Institute (cc-by)
- Funders
- BrightFocus Foundation (A2015275S)
- Wellcome Trust (FP7/2007–2013, 098330, 608765, 098330/Z/12/Z, 217199, 217199/Z/19/Z, 098327/Z/12/Z)
- Francis Crick Institute (10194)
- EU Joint Programme – Neurodegenerative Disease Research
- Alzheimer's Society
- Zaklade Adris
- Parkinson's UK (G-0907)
- European Commission (608765, GA KK 01 1 1 01 0007, 2007–2013, FP7 2007-2013, FP7/2007, IP-2019-04-3584)
- Rosetrees Trust
- National Research Foundation (NRF-NRFF2016-03)
- National Research Foundation Singapore (NRFF2016, NRF-NRFF2016-03)
- Agence Nationale de la Recherche (ANR-17-JPCD-0003)
- Royal Swedish Academy of Sciences (2017-00915)
- Fondation pour la Recherche Médicale
- Hjärnfonden (FO2017‑0243, FO2017, ALFGBG-715986)
- Vetenskapsrådet (FP7/2007-2013, 2017-00915, (#ALFGBG-715986, ALFGBG-720931, FO2017-0243)
- Hrvatska Zaklada za Znanost (IP-2019-04, IP-2016-06-9451, PZS-2019-02-4277, IP-2019-04-3584, GA KK01.1.1.01.0007, KK01.1.1.01.0007, 2019‐04‐3584)
- UK Dementia Research Institute (#2017-00915, ALFGBG-715986, FO2017-0243, -0243, -715986)
- National Institutes of Health (IP-2019-04-3584, FP7/2007-2013, 1rf1ag059695-01a1, KK.01.1.1.01.0007, GA KK01.1.1.01.0007)
- Medical Research Council (FP7/20072013, MR/L501542/1, MR/S011277/1, MR/R024901/1, MR/N026004/1, 608765, MR/T002581/1)
- National Medical Research Council (NMRC/CIRG/1438/ 2015)
- European Regional Development Fund (GA KK01.1.1.01.0007, FP7/2007‐2013, 2007 – 2013, KK.01.1.1.01.0007, IP-2019-04-3584)
- National Institute on Aging (RF1 AG059695)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Down syndrome and intellectual disability research
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- Down syndrome, Alzheimer's disease, BACE2, brain organoids, amyloid-beta, tau hyperphosphorylation, BACE1 inhibitors, gene dosage, beta-secretase inhibition, gamma-secretase inhibition, cerebrospinal fluid biomarkers, neurodegeneration, drug screening
- MeSH terms
- Alzheimer Disease, Brain, Down Syndrome, Humans, Organoids, Trisomy, Genes, Suppressor, Amyloid beta-Peptides, Aspartic Acid Endopeptidases, Amyloid Precursor Protein Secretases
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