Human iPSC-derived APOE4/4 Alzheimer´s disease astrocytes exhibit a proinflammatory and senescent state that compromise neuronal support

Abstract

Background: Alzheimer's disease (AD) is characterized by a complex pathology, not fully resolved yet. This fact, together with the lack of reliable models, has impeded the development of effective therapies. Glial cell dysfunction has been proposed to be involved in AD pathogenesis, but this cannot be properly modeled using the available animal models, so we hypothesized that cells derived from AD patients can serve as a better platform for studying the disease. In this sense, human pluripotent stem cells (hPSC) allow the generation of different types of neural cells, which can be used for disease modeling, identification of new targets and drugs development. Methods: We have generated hiPSC-derived astrocytes from AD patients and cognitively unimpaired agematched individuals and evaluated their metabolism and phenotype employing confocal imaging, immunofluorescence, flow cytometry, RT-qPCR and functional assays. Results: All astrocytes expressed functional markers including aldehyde dehydrogenase 1A1 (ALDH1A1), glutamate transporter GLAST, glial fibrillary acidic protein (GFAP), aquaporin-4 (AQP4) and vimentin. However, astrocytes from AD patients showed increased expression of reactive markers. In addition, these astrocytes derived from AD patients showed significant metabolic alterations associated with a pro-inflammatory and senescent phenotype which in turn impair their neuronal support as measured in coculture assays. Conclusions: Our preliminary data suggest that astrocytes derived from AD patients present an intrinsic proinflammatory and senescent phenotype which compromise their functionality. Elucidating the mechanisms inducing these processes and their functional consequences should help for a better understanding of role that astrocytes play in AD, by direct functioning and also through their interactions with neurons and the other glial cells. This should lead to the identification of potential therapeutic targets for future AD treatments.