Dissecting the role of human astroglia in Alzheimer’s disease pathogenesis

In contrast to neurons, astrocytes are not very well investigated in Alzheimer’s disease (AD). This is remarkable: the most important genetic risk factor for AD is ApoE4 which is mainly expressed by these cells. Moreover, astrocytes are the most numerous cell type in brain and are affected at the early stages of the disease. The current understanding of astrocyte physiology is almost entirely restricted to observations in rodent models. Recent studies show that human astrocytes are far more complex and behave very differently than their rodent counterparts. Chimeric mice generated by implanting human astrocytes in the brain display enhanced synaptic functions and show better performance in learning and memory tests (Han et al., 2013). This, and knowing that mouse models recapitulate well the biochemical but not the cellular alterations of AD, raises the following questions. Are there distinct properties of human astrocytes that modulate AD pathogenesis? How will human astrocytes influence the AD pathology in mouse models? And can we extend findings about astrocyte pathology in AD from studies in rodents only, to develop effective therapeutic approaches for patients? Here, we will use stem-cell technology to generate human astrocytes and to transplant them in the brain of AD mice to generate chimeric AD human-mouse models. Further analysis will show how human astrocytes react on and modulate AD pathology in live adult brain, which will provide entirely novel insights for AD.