Patient-specific Alzheimer-like pathology in trisomy 21 cerebral organoids reveals BACE2 as a gene dose-sensitive AD suppressor in human brain
Creators: name: Alić, Ivan
name: Goh, Pollyanna A
name: Murray, Aoife
name: Portelius, Erik
name: Gkanatsiou, Eleni
name: Gough, Gillian
name: Mok, Kin Y
name: Koschut, David
name: Brunmeir, Reinhard
name: Yeap, Yee Jie
name: O’Brien, Niamh L
name: Groet, Jürgen
name: Shao, Xiaowei
name: Havlicek, Steven
name: Dunn, N Ray
name: Kvartsberg, Hlin
name: Brinkmalm, Gunnar
name: Hithersay, Rosalyn
name: Startin, Carla
name: Hamburg, Sarah
name: Phillips, Margaret
name: Pervushin, Konstantin
name: Turmaine, Mark
name: Wallon, David
name: Rovelet-Lecrux, Anne
name: Soininen, Hilkka
name: Volpi, Emanuela
name: Martin, Joanne E
name: Foo, Jia Nee
name: Becker, David L
name: Rostagno, Agueda
name: Ghiso, Jorge
name: Krsnik, Željka
name: Šimić, Goran
name: Kostović, Ivica
name: Mitrečić, Dinko
name: Consortium, LonDownS
name: Francis, Paul T
name: Blennow, Kaj
name: Strydom, Andre
name: Hardy, John
name: Zetterberg, Henrik
name: Nižetić, Dean
Publisher: name: The Francis Crick Institute
Year: 2022
Subjects: classificationCode: Model organisms
subject: Model organisms
classificationCode: Signalling & Oncogenes
subject: Signalling &amp; Oncogenes
classificationCode: Developmental Biology
subject: Developmental Biology
classificationCode: Human Biology & Physiology
subject: Human Biology &amp; Physiology
classificationCode: Cell Biology
subject: Cell Biology
classificationCode: Immunology
subject: Immunology
subject: FOS: Clinical medicine

description: 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.