期刊
MOLECULAR PSYCHIATRY
卷 26, 期 10, 页码 5766-5788出版社
SPRINGERNATURE
DOI: 10.1038/s41380-020-0806-5
关键词
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资金
- Singapore National Medical Research Council [NMRC/CIRG/1438/2015]
- Singapore Ministry of Education Academic Research Fund Tier 2 grants [2015-T2-1-023, 2015-T2-2-119]
- Wellcome Trust Collaborative Award in Science [217199/Z/19/Z]
- Research Cooperability Programme of the Croatian Science Foundation [PZS-2019-02-4277]
- EU-JPND-Heroes Consortia
- EU-JPND-CoEN Consortia
- Wellcome Trust LonDownS Consortium Strategic Funding Award (UK) [098330/Z/12/Z]
- Dementia Research Institute
- Dolby foundation
- Swedish Research Council [2017-00915]
- European Research Council
- Swedish State Support for Clinical Research [ALFGBG-720931, ALFGBG-715986]
- UK Dementia Research Institute at UCL
- Torsten Soderberg Professorship in Medicine at the Royal Swedish Academy of Sciences
- Swedish Alzheimer Foundation [AF-742881]
- Hjarnfonden, Sweden [FO2017-0243]
- People Programme (Marie Curie Actions) of the European Union's Seventh Framework Programme (FP7/2007-2013) under REA grant [608765]
- Singapore National Research Foundation [NRF-NRFF2016-03]
- Fondation pour la Recherche Medicale (FRM)
- BrightFocus Foundation [A2015275S]
- NIH [AG059695]
- Scientific Centre of Excellence for Basic, Clinical and Translational Neuroscience (project Experimental and clinical research of hypoxic-ischemic damage in perinatal and adult brain - European Union through the European Regional Development Fund) [GA KK01.1.1.01.0007]
- Adris Foundation
- Croatian Science Foundation [HRZZ IP-2019-04-3584, IP-2016-06-9451]
- Alzheimer's Research UK
- Alzheimer's Society
- BRACE (Bristol Research into Alzheimer's and Care of the Elderly)
- Medical Research Council, UK
- MRC [G0701075, MR/R024901/1, G0901254, MR/N026004/1, MR/S011277/1, UKDRI-1009] Funding Source: UKRI
- Wellcome Trust [217199/Z/19/Z] Funding Source: Wellcome Trust
Research has shown that individuals with Down Syndrome exhibit Alzheimer's disease-like pathological changes, which can be successfully replicated in vitro cerebral organoids models. These findings suggest that DS cerebral organoids could serve as a potential detector for pre-morbid AD-risk populations, as well as a system for hypothesis-free drug screening and identification of natural suppressor genes for neurodegenerative diseases.
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 beta-amyloid-(A beta)-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 A beta 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 beta and gamma-secretase inhibition. We found that T21 organoids secrete increased proportions of A beta-preventing (A beta 1-19) and A beta-degradation products (A beta 1-20 and A beta 1-34). 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 similar to 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.
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