Aß, Tau and neuronal death in a novel humanized mouse model for Alzheimer Disease

The relationship between Amyloid ɴ(Aɴpeptide, Tau, and neuronal cell loss is a central problem in the study of Alzheimer’s disease (AD). However, cell culture or animal models do not reproduce well the cell death phenotype that is crucial to analyze this relation. As it remains unclear to what extent rodent or other species can fully reproduce the AD phenotype, such study is performed ideally in human cells. In the current project, we take full advantage of our recently developed the humanized model for AD. Human stem cell-derived, differentiated cortical neurons representing all cortical layers show the induction of Tau pathology and massive neuronal cell death upon exposure to Aɴin the context of the mouse brain. We propose to study the role of Tau in inducing the neuronal cell death as well as to perform a Crisper/Cas9 based human kinase screen in these human neurons to identify modifiers of the neuronal death phenotype in vivo. Such a screen on fully matured human neurons not overexpressing any of the known AD genes has direct relevance for the human situation. We will further investigate the role of identified hits by rescue experiments in our humanized AD model and analyze their expression in human brain material. The experiments will provide direct targets to treat the cell death in Alzheimer disease.