Naslov
Patient-specific Alzheimer-like pathology in trisomy 21 cerebral organoids reveals BACE2 as a gene dose-sensitive AD suppressor in human brain

Autori
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. ; Groet, Jürgen ; Shao, Xiaowei ; Havlicek, Steven ; Dunn, N. Ray ; Kvartsberg, Hlin ; Brinkmalm, Gunnar ; Hithersay, Rosalyn ; Startin, Carla ; Hamburg, Sarah ; Phillips, Margaret ; Pervushin, Konstantin ; Turmaine, Mark ; Wallon, David ; Rovelet-Lecrux, Anne ; 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 ; LonDownS Consortium ; Francis, Paul T. ; Blennow, Kaj ; Strydom, Andre ; Hardy, John ; Zetterberg, Henrik ; Nižetić, Dean

Izvornik
Molecular psychiatry (1359-4184) 26 (2021); 5766-5788

Vrsta, podvrsta i kategorija rada
Radovi u časopisima, članak, znanstveni

Ključne riječi
Alzheimer ; cerebral organoids

Sažetak
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 βamyloid-(Aβ)-precursor-protein gene. We report AD-like pathology in cerebral organoids grown in vitro from noninvasively 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.

Izvorni jezik
Engleski

Znanstvena područja
Temeljne medicinske znanosti

POVEZANOST RADA