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Neuron. 2017 Mar 8;93(5):1066-1081.e8. doi: 10.1016/j.neuron.2017.02.001. Epub 2017 Feb 23.

Hallmarks of Alzheimer's Disease in Stem-Cell-Derived Human Neurons Transplanted into Mouse Brain.

Author information

1
VIB Center for Brain and Disease Research, VIB-Leuven, 3000 Leuven, Belgium; Center for Human Genetics, Universitaire ziekenhuizen and LIND, KU Leuven, 3000 Leuven, Belgium.
2
VIB Center for Brain and Disease Research, VIB-Leuven, 3000 Leuven, Belgium; Center for Human Genetics, Universitaire ziekenhuizen and LIND, KU Leuven, 3000 Leuven, Belgium. Electronic address: amaia.arranz@kuleuven.vib.be.
3
Laboratory of Histology, Neuroanatomy and Neuropathology and ULB Neuroscience Institute (UNI), Université Libre de Bruxelles, 1070, Brussels, Belgium.
4
VIB Center for Brain and Disease Research, VIB-Leuven, 3000 Leuven, Belgium; Center for Human Genetics, Universitaire ziekenhuizen and LIND, KU Leuven, 3000 Leuven, Belgium; VIB Bio Imaging Core, KU Leuven, Herestraat 49, 3000 Leuven, Belgium.
5
Université Libre de Bruxelles (ULB), Institute for Interdisciplinary Research (IRIBHM), and ULB Institute of Neuroscience (UNI), 1070 Brussels, Belgium.
6
Laboratory of Neurophysiology and ULB Neuroscience Institute (UNI), 808 Route de Lennik, 1070 Brussels, Belgium.
7
Institute of Neurology and Dementia Research Institute, University College London, Queen Square, WC1N 3BG London, UK.
8
Neuroscience Department, Johnson & Johnson Pharmaceutical Research and Development, Janssen Pharmaceutica, Turnhoutseweg 30, 2340 Beerse, Belgium.
9
VIB Center for Brain and Disease Research, VIB-Leuven, 3000 Leuven, Belgium; Université Libre de Bruxelles (ULB), Institute for Interdisciplinary Research (IRIBHM), and ULB Institute of Neuroscience (UNI), 1070 Brussels, Belgium; WELBIO, Université Libre de Bruxelles, 1070 Brussels, Belgium. Electronic address: pvdhaegh@ulb.ac.be.
10
VIB Center for Brain and Disease Research, VIB-Leuven, 3000 Leuven, Belgium; Center for Human Genetics, Universitaire ziekenhuizen and LIND, KU Leuven, 3000 Leuven, Belgium; Institute of Neurology and Dementia Research Institute, University College London, Queen Square, WC1N 3BG London, UK. Electronic address: bart.destrooper@vib.be.

Abstract

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.

KEYWORDS:

Alzheimer’s disease; cell death; chimeric mouse; dystrophic neurites; expression analysis; human neurons; modeling; neurodegeneration; pluripotent stem cells

PMID:
28238547
DOI:
10.1016/j.neuron.2017.02.001
[Indexed for MEDLINE]
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