Stem-Cell Derived Human Neurons in Mouse Brain to Model Alzheimer’s Disease

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.

Original paper:
http://www.sciencedirect.com/science/article/pii/S0896627317300582

also see:
http://www.nature.com/nrneurol/journal/vaop/ncurrent/full/nrneurol.2017.37.html

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