Induction of tau pathology, tangles and necroptosis in human neurons exposed to amyloid plaques in chimeric mouse brain

Background Modeling Alzheimer's disease in animal models has been difficult. Method We generated human/mouse chimeric animal models. The mice are Rag2‐/‐, AppNL‐K‐F and develop gradually amyloid plaques, starting from 2 months. We transplanted human neuronal precursor cells into the brain of newborn pubs. Result The neurons integrate into the brain of the mice, and mature to synaptic active neurons. In the control mice they remain healthy up to 18 months. In the amyloid expressing mice the human neurons develop abnormal Tau phosphorylation, tangles and eventually die. The neurons show granulovacuolar neurodegeneration and characteristics of necroptosis. There is microglia and astrogliosis, but these are largely murine cells although older grafts also show human astrogliosis and an oligodendrocyte component that needs further evaluation. Conclusion This is a very complete model of AD with human neurons developing all pathological characteristics of AD. The experiment also demonstrate that exposure of human neurons to amyloid plaques is sufficient to induce the full spectrum of AD pathology.