hiPSC-based models to decipher the contribution of human astrocytes to Alzheimer’s disease and potential therapeutics

Astrocytes constitute a large part of the brain cell mass and play essential functions in the central nervous system. They provide trophic and metabolic support to neurons, regulate synapse formation, neurotransmission, calcium homeostasis, and control immune response and blood flow. In Alzheimer’s disease (AD), astrocytes undergo profound molecular, morphological and functional alterations that arise at early stages and exacerbate as disease evolves, indicating that astrocytes transition from homeostatic to dysfunctional disease-associated states and pointing to these cells as critical contributors to AD progression. Genome-wide association studies (GWAS) support this idea as many genes associated with increasing the risk of developing late-onset AD (LOAD) are expressed in glial cells: astrocytes, microglia and oligodendrocytes [1]. Among those, major AD risk genes such as APOE, CLU and FERMT2 are predominantly expressed in astrocytes [1]. While our current knowledge of astrocyte contribution to AD is mainly coming from studies in mouse models, critical species-specific differences highlight the importance of studying astrocyte (dys)function in human-based systems. The ability to generate human induced pluripotent stem cells (hiPSCs) from patients and differentiate them into astrocytes is providing exciting opportunities to explore their functions in AD. We summarize recent studies in 2D and 3D cultures that provide essential clues on the impact of human astrocytes on AD and propose potential astrocyte-targeting therapeutics.