Journal Article

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

Turmaine, Mark, Groet Jürgen, Rovelet-Lecrux Anne, Koschut, David, Ray, Dunn N, Alić Ivan, Gkanatsiou Eleni, Mok, Kin Y, Rostagno Agueda, Zetterberg Henrik, Hardy, John, Yeap Yee Jie, Krsnik Željka, Kostović Ivica, Strydom, Andre, Murray, Aoife, Nizetic Dean, Blennow Kaj, Goh, Pollyanna A, Nižetić Dean, Tybulewicz Victor, Hithersay Rosalyn, Portelius Erik, Martin, Joanne E, Soininen Hilkka, Brunmeir Reinhard, Gough, Gillian, O’Brien Niamh L, Havlicek, Steven, Wallon, David, Wiseman, Frances, Foo Jia Nee, Hlin, Kvartsberg, Becker, David L, Fisher, Elizabeth, Startin Carla, Šimić Goran, Pervushin Konstantin, Volpi Emanuela, Brinkmalm Gunnar, Mitrečić Dinko, Karmiloff-Smith, Annette, Shao Xiaowei, Francis, Paul T, Hamburg, Sarah, Ghiso Jorge, Phillips, Margaret

2021

Overview

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.

• Publisher: Nature Publishing Group
• Subject: Alzheimer's disease / Cerebrospinal fluid / Chromosome 21 / CRISPR / Degradation products / Dementia / Dementia disorders / Down's syndrome / Drug screening / Neurodegenerative diseases / Organoids / Pathology / Secretase / Tau protein / Trisomy / β-Amyloid / β-Site APP-cleaving enzyme 1 / β-Site APP-cleaving enzyme 2