| Autor: |
Jorge Ghiso, Agueda Rostagno, Steven Havlicek, Sarah Hamburg, Ivan Alić, Carla M. Startin, Rosalyn Hithersay, Eleni Gkanatsiou, David Koschut, Hlin Kvartsberg, Hilkka Soininen, Emanuela V. Volpi, Xiaowei Shao, Goran Šimić, Željka Krsnik, Dean Nižetić, Mark Turmaine, Joanne E. Martin, Jürgen Groet, Aoife Murray, Erik Portelius, Pollyanna Goh, Jia Nee Foo, Niamh L. O'Brien, Henrik Zetterberg, Andre Strydom, Yee Jie Yeap, David Wallon, Gillian Gough, John Hardy, Margaret Phillips, N. Ray Dunn, Dinko Mitrečić, Gunnar Brinkmalm, Reinhard Brunmeir, Kin Y. Mok, Anne Rovelet-Lecrux, Kaj Blennow, Ivica Kostović, Konstantin Pervushin, Paul T. Francis, David Laurence Becker |
| Jazyk: |
angličtina |
| Rok vydání: |
2020 |
| Předmět: |
|
| DOI: |
10.1101/2020.01.29.918037 |
| Popis: |
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 grownin vitrofrom 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-geneBACE2, 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 ofBACE2as 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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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