An in vivo humanized model for Alzheimer’s disease from pluripotent stem cells

The generation of in vitro and in vivo models to study human corticogenesis is essential to address the molecular and cellular mechanisms involved in developmental and degenerative cortical diseases. We previously found that human pluripotent stem cells (PSC) can recapitulate major milestones of human corticogenesis in vitro. In addition, following the transplantation of human PSC-derived cortical cells into the mouse neonatal brain we observed a functional integration and establishment of specific axonal projections from the human neurons.
Several neurological diseases strike the integrity of the cerebral cortex including stroke, epilepsy and neurodegenerative diseases such as Alzheimer’s disease (AD). When some of these diseases have been extensively studied, mostly they have been tackled using murine transgenic models that cannot completely recapitulate the etiology of the disease.
Here, we present a novel “in vivo humanized AD model” from human pluripotent stem cells. We transplanted PSC-derived human cortical neurons into the brain of transgenic AD mouse models to characterize early and late effects of amyloid pathology on human neurons. We found that human neurons exposed to the toxic amyloid-beta species in the transgenic mouse brain show very early signs of neurodegeneration, including aberrant accumulation of pre-synaptic neurotransmitter vesicles, and early neuronal loss. Signs of neuronal and axonal degeneration were also observed by EM analysis specifically in the human neurons. Interestingly, the human neurons located at amyloid-beta plaque sites were positive for pathological Tau tangle-like staining, a major hallmark of AD. A preliminary comparative RNA expression analysis at early stages between human neurons transplanted into wild-type and transgenic animals revealed some differentially expressed candidate genes that could shed new light on the biology of early stages of the disease.
In conclusion, the humanized model for AD can recapitulate major milestones of the AD human pathology in an in vivo context and could be instrumental for the study of early and late stages of the pathology, opening new venues for future research in the field.
Overall, these data demonstrate that cortical neurons derived from human pluripotent stem cells represent an invaluable tool for the modeling of human cortical diseases, in particular adult onset, human specific neurological disorders, such as Alzheimer’s disease.