Journal
NEURON
Volume 93, Issue 5, Pages 1066-+Publisher
CELL PRESS
DOI: 10.1016/j.neuron.2017.02.001
Keywords
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Funding
- European Research Council [ERC-2010-AG_268675]
- Fonds voor Wetenschappelijk Onderzoek (FWO)
- KU Leuven
- VIB
- KU Leuven/Flemish Government
- Bax-Vanluffelen Chair for Alzheimer's Disease and Opening the Future of the Leuven Universiteit Fonds (LUF)
- Vlaams Initiatief voor Netwerken voor Dementie Onderzoek (VIND) [135043]
- Belgian Queen Elizabeth Medical Foundation
- WELBIO Program of the Walloon Region
- Fondation de SPOELBERCH
- AXA Research Fund
- Fondation ULB
- Belgian Fonds de la Recherche Scientifique Medicale [T.0023.15]
- Fund Aline (King Baudoin Foundation)
- Foundation for Alzheimer Research [FRA/SAO] [14001]
- Fund Genicot [ULB - 2015]
- IAP program of the Belgian Federal Science Policy Office [P7/16, P7/20]
- NIHR Queen Square Dementia Biomedical Research Unit
- Janssen Pharmaceutics
- [ERC-2013 ERC-2013-AG_340020]
- [1.B.007.15]
- MRC [MC_PC_17116, G1001253, G0701075, MR/J004758/1, MR/K01417X/1, G0901254] Funding Source: UKRI
- Medical Research Council [MC_PC_17116] Funding Source: researchfish
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Human pluripotent stem cells (PSCs) provide a unique entry to study species-specific aspects of human disorders such as Alzheimer's disease (AD). However, in vitro culture of neurons deprives them of their natural environment. Here we transplanted human PSC-derived cortical neuronal precursors into the brain of a murine AD model. Human neurons differentiate and integrate into the brain, express 3R/4R Tau splice forms, show abnormal phosphorylation and conformational Tau changes, and undergo neurodegeneration. Remarkably, cell death was dissociated from tangle formation in this natural 3D model of AD. Using genome-wide expression analysis, we observed upregulation of genes involved in myelination and downregulation of genes related to memory and cognition, synaptic transmission, and neuron projection. This novel chimeric model for AD displays human-specific pathological features and allows the analysis of different genetic backgrounds and mutations during the course of the disease.
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