Old, from 2017: Hallmarks of Alzheimer’s Disease in Stem-Cell-Derived Human Neurons Transplanted into Mouse Brain

Old, from 2017: Hallmarks of Alzheimer’s Disease in Stem-Cell-Derived Human Neurons Transplanted into Mouse Brain. Ira Espuny-Camacho et al. Neuron, Volume 93, ISSUE 5, P1066-1081.e8 DOI:https://doi.org/10.1016/j.neuron.2017.02.001

Highlights
    Human-mouse chimeric model of Alzheimer’s disease
    PSC-derived human neurons grafted into an AD mouse
    Major degeneration and loss of human neurons in chimeric AD mice
    Absence of tangle pathology in degenerating human neurons in vivo

Summary: 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.