Patient-specific Alzheimer-like pathology in trisomy 21 cerebral organoids reveals BACE2 as a gene-dose-sensitive AD-suppressor in human brain
By
Ivan Alić,
Pollyanna A Goh,
Aoife Murray,
Erik Portelius,
Eleni Gkanatsiou,
Gillian Gough,
Kin Y Mok,
David Koschut,
Reinhard Brunmeir,
Yee Jie Yeap,
Niamh O'Brien,
Jurgen Groet,
Xiaowei Shao,
Steven Havlicek,
N Ray Dunn,
Hlin Kvartsberg,
Gunnar Brinkmalm,
Rosalyn Hithersay,
Carla Startin,
Sarah Hamburg,
Margaret Phillips,
Konstantin Pervushin,
Mark Turmaine,
David Wallon,
Anne Rovelet-Lecrux,
Hilkka Soininen,
Emanuela Volpi,
Joanne E Martin,
Jia Nee Foo,
David L Becker,
Agueda Rostagno,
Jorge Ghiso,
Željka Krsnik,
Goran Šimić,
Ivica Kostović,
Dinko Mitrečić,
LonDownS Consortium,
Paul T Francis,
Kaj Blennow,
Andre Strydom,
John Hardy,
Henrik Zetterberg,
Dean Nižetić
Posted 31 Jan 2020
bioRxiv DOI: 10.1101/2020.01.29.918037
(published DOI: 10.1038/s41380-020-0806-5)
A population of >6 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.
Download data
- Downloaded 619 times
- Download rankings, all-time:
- Site-wide: 41,042
- In neuroscience: 5,843
- Year to date:
- Site-wide: 47,186
- Since beginning of last month:
- Site-wide: 64,558
Altmetric data
Downloads over time
Distribution of downloads per paper, site-wide
PanLingua
News
- 27 Nov 2020: The website and API now include results pulled from medRxiv as well as bioRxiv.
- 18 Dec 2019: We're pleased to announce PanLingua, a new tool that enables you to search for machine-translated bioRxiv preprints using more than 100 different languages.
- 21 May 2019: PLOS Biology has published a community page about Rxivist.org and its design.
- 10 May 2019: The paper analyzing the Rxivist dataset has been published at eLife.
- 1 Mar 2019: We now have summary statistics about bioRxiv downloads and submissions.
- 8 Feb 2019: Data from Altmetric is now available on the Rxivist details page for every preprint. Look for the "donut" under the download metrics.
- 30 Jan 2019: preLights has featured the Rxivist preprint and written about our findings.
- 22 Jan 2019: Nature just published an article about Rxivist and our data.
- 13 Jan 2019: The Rxivist preprint is live!