[en] 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
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Espuny Camacho, Ira Mercedes ; VIB-Leuven, KU Leuven, 3000 Leuven, Belgium > VIB Center for Brain and Disease Research, Center for Human Genetics
Arranz, AM; VIB-Leuven, KU Leuven, 3000 Leuven, Belgium > VIB Center for Brain and Disease Research, Center for Human Genetics
Fiers, M; VIB Leuven, KU Leuven > VIB Center for Brain and Disease Research, Center for Human Genetics
Snellinx, A; VIB-Leuven, KU Leuven, 3000 Leuven, Belgium > VIB Center for Brain and Disease Research, Center for Human Genetics
Ando, K; Université Libre de Bruxelles, 1070, Brussels, Belgium. > Laboratory of Histology, Neuroanatomy and Neuropathology and ULB Neuroscience Institute (UNI)
Munck, S; VIB-Leuven, KU Leuven, 3000 Leuven, Belgium > VIB Center for Brain and Disease Research, Center for Human Genetics
Bonnefont, J; Université Libre de Bruxelles (ULB), 1070 Brussels, Belgium > Institute for Interdisciplinary Research (IRIBHM), and ULB Institute of Neuroscience (UNI)
Lambot, L; Université Libre de Bruxelles (ULB), 808 Route de Lennik, 1070 Brussels, Belgium. > Laboratory of Neurophysiology and ULB Neuroscience Institute (UNI),
Corthout, N; VIB-Leuven, KU Leuven, 3000 Leuven, Belgium > VIB Center for Brain and Disease Research, Center for Human Genetics
Omodho, L; VIB-Leuven, KU Leuven, 3000 Leuven, Belgium > VIB Center for Brain and Disease Research, Center for Human Genetics
Vanden Eynden, E; VIB-Leuven, KU Leuven, 3000 Leuven, Belgium > VIB Center for Brain and Disease Research, Center for Human Genetics
Radaelli, E; VIB-Leuven, KU Leuven, 3000 Leuven, Belgium > VIB Center for Brain and Disease Research, Center for Human Genetics
Tesseur, I; VIB-Leuven, KU Leuven, 3000 Leuven, Belgium > VIB Center for Brain and Disease Research, Center for Human Genetics
Wray, S; University College London, Queen Square, WC1N 3BG London, UK. > Institute of Neurology and Dementia Research Institute
Ebneth, A; Janssen Pharmaceutica, Turnhoutseweg 30, 2340 Beerse, Belgium > Neuroscience Department, Johnson & Johnson Pharmaceutical Research and Development,
Hardy, J; University College London, Queen Square, WC1N 3BG London, UK > Institute of Neurology and Dementia Research Institute
Leroy, K; Université Libre de Bruxelles, 1070, Brussels, Belgium. > Laboratory of Histology, Neuroanatomy and Neuropathology and ULB Neuroscience Institute (UNI)
Brion, JP; Université Libre de Bruxelles, 1070, Brussels, Belgium. > Laboratory of Histology, Neuroanatomy and Neuropathology and ULB Neuroscience Institute (UNI)
Vanderhaeghen, P; VIB-Leuven, 3000 Leuven, Belgium ; Université Libre de Bruxelles (ULB), 1070 Brussels, Belgium ; WELBIO, Université Libre de Bruxelles, 1070 Brussels, Belgium > VIB Center for Brain and Disease Research, Institute for Interdisciplinary Research (IRIBHM), and ULB Institute of Neuroscience (UNI)
De Strooper, B; VIB-Leuven, KU Leuven, 3000 Leuven, Belgium > VIB Center for Brain and Disease Research, Center for Human Genetics
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