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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
Alić I, Goh PA, Murray A, Portelius E, Gkanatsiou E, Gough G, Mok KY, Koschut D et al.. Molecular psychiatry, 2020-07-10
Topic: Brain proteins, microglia and lab models
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.
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
APA 7th
Alić, I., Goh, P. A., Murray, A., Portelius, E., Gkanatsiou, E., Gough, G., et al. (2021). Patient-specific Alzheimer-like pathology in trisomy 21 cerebral organoids reveals BACE2 as a gene dose-sensitive AD suppressor in human brain. Molecular psychiatry. https://doi.org/10.1038/s41380-020-0806-5
Vancouver
Alić I, Goh PA, Murray A, Portelius E, Gkanatsiou E, Gough G, et al. Patient-specific Alzheimer-like pathology in trisomy 21 cerebral organoids reveals BACE2 as a gene dose-sensitive AD suppressor in human brain. Molecular psychiatry. 2021. doi:10.1038/s41380-020-0806-5. PMID: 32647257.
BibTeX
@article{alic2021-32647257,
author = {Alić, I. and Goh, P. A. and Murray, A. and Portelius, E. and Gkanatsiou, E. and Gough, G. and Mok, K. Y. and Koschut, D. and others},
title = {{Patient-specific Alzheimer-like pathology in trisomy 21 cerebral organoids reveals BACE2 as a gene dose-sensitive AD suppressor in human brain}},
journal = {Molecular psychiatry},
year = {2021},
doi = {10.1038/s41380-020-0806-5},
pmid = {32647257},
url = {https://doi.org/10.1038/s41380-020-0806-5}
}
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. The record's author list ends in “et al.”, so not every author is named. Check the citation against the original before you use it.
Key findings
- We found that T21 organoids secrete increased proportions of Aβ-preventing (Aβ1-19) and Aβ-degradation products (Aβ1-20 and Aβ1-34).
Why it matters
In brain organoids grown from hair samples of people with Down syndrome, Alzheimer-like amyloid and tau changes appeared for 71% of donors, and whether a donor's organoids showed them was consistent across repeat experiments. In organoids that had no such changes, removing the extra copy of the BACE2 gene caused them to appear, and the authors report a matching pattern of amyloid fragments in the spinal fluid of people with Down syndrome. They propose that the extra BACE2 copy acts as a brake on Alzheimer pathology that may help explain why about 30% of people with Down syndrome have delayed dementia. This is lab-dish work, not a test or a treatment.
Study details
- Evidence strengthLow
Limitations
These are lab-grown organoids, not actual human brains, so how faithfully they reproduce real disease progression, and whether findings in them will translate to patients, is not established by this study alone.
How this study scored 53/100
Published in a leading specialty journal. Scored zero for study design, sample size, effect reported and randomized / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 9 / 10 | Tier 2 — leading specialty journal (Molecular psychiatry) |
| Journal's citation record | 3 / 4 | Molecular Psychiatry: journal h-index 318 (OpenAlex, 2026-10-29) |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 3 / 5 | 2021 — within 6 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Laboratory or animal study (title names “organoids”) — scores zero |
| Randomized / blinded | 0 / 2 | No randomization or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 5 / 7 | Cited 122 times (OpenAlex, 2026-10-10) |
| Citations per year | 3 / 5 | 17.4 citations a year over 7 year(s) since 2021 |
| Impact for its field and year | 4 / 6 | Cited 9.0× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 2 / 6 | Cited by 7 other studies in this library |
| Still being cited | 2 / 4 | Cited 49 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 2 / 4 | Last-listed author Dean Nižetić: h-index 43 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | University College London: institution h-index 2,029 (OpenAlex) |
| Multicenter collaboration | 3 / 3 | OpenAlex lists 21 institution(s) in 7 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 32647257) |
| Free to read | 2 / 2 | Free to read |
| Total | 53 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
- DOI: 10.1038/s41380-020-0806-5
- PubMed: 32647257
- Original source →
- Free full text: Molecular Psychiatry →
Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).
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