Patient-specific Alzheimer-like pathology in trisomy 21 cerebral organoids reveals BACE2 as a gene dose-sensitive AD suppressor in human brain
| Autor: | Jia Nee Foo, Andre Strydom, Xiaowei Shao, David Koschut, Goran Šimić, Željka Krsnik, Sarah Hamburg, Ivan Alić, Steven Havlicek, Hlin Kvartsberg, Jürgen Groet, Paul T. Francis, Yee Jie Yeap, Pollyanna Goh, Hilkka Soininen, Rosalyn Hithersay, John Hardy, Niamh L. O'Brien, Margaret Phillips, David Laurence Becker, N. Ray Dunn, Gunnar Brinkmalm, David Wallon, Gillian Gough, Henrik Zetterberg, Erik Portelius, Mark Turmaine, Aoife Murray, Jorge Ghiso, Kaj Blennow, Eleni Gkanatsiou, Agueda Rostagno, Carla M. Startin, Ivica Kostović, Konstantin Pervushin, Emanuela V. Volpi, Dean Nižetić, Joanne E. Martin, Dinko Mitrečić, Reinhard Brunmeir, Kin Y. Mok, Anne Rovelet-Lecrux |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Pathology Diseases Trisomy cerebral organoid 0302 clinical medicine β-secretase Aspartic Acid Endopeptidases Genes Suppressor education.field_of_study Human Biology & Physiology biology BACE2 Brain Human brain trisomy 21 Organoids Psychiatry and Mental health medicine.anatomical_structure Model organisms Down syndrome medicine.medical_specialty Amyloid beta Population Immunology BACE-inhibitor Alzheimer cerebral organoids Article 03 medical and health sciences Cellular and Molecular Neuroscience Signalling & Oncogenes Alzheimer Disease medicine Organoid Genetics Dementia Humans education Molecular Biology Amyloid beta-Peptides business.industry FOS: Clinical medicine Cell Biology medicine.disease 030104 developmental biology biology.protein Amyloid Precursor Protein Secretases Down Syndrome business Chromosome 21 030217 neurology & neurosurgery Neuroscience Developmental Biology |
| Zdroj: | Molecular Psychiatry |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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