Human astrocytes carrying APOE3 or APOE4 variants have distinct effects on Alzheimer’s disease
A research team from the Humanized Models of Disease Laboratory, led by Ikerbasque Professor Amaia Arranz, has published a new study in Cell Reports entitled “Human APOE3 and APOE4 astrocytes differentially modulate Alzheimer’s disease pathology and microglial responses in chimeric mice.”
The study investigated how human astrocytes carrying different APOE variants, the most important genetic risk factor for sporadic Alzheimer’s disease, influence key pathological features of the disease.
To study these effects directly in human cells within the living brain, the researchers developed humanized chimeric models of Alzheimer’s disease. Human induced pluripotent stem cell (hiPSC)-derived astrocyte progenitors carrying either APOE3 or APOE4 were transplanted into the brains of neonatal Alzheimer’s disease-model mice. The human cells matured into astrocytes, integrated into the mouse brain and interacted with surrounding host cells, providing a unique model to investigate the contribution of human astrocytes to Alzheimer’s pathology in vivo.
The results revealed striking differences depending on the APOE variant. Human astrocytes carrying APOE3 had a protective effect, reducing amyloid-beta pathology, Tau-associated pathology and neuronal damage, whereas APOE4 astrocytes promoted a more detrimental environment and exacerbated several pathological features of the disease.
Importantly, the effects of human astrocytes extended beyond Alzheimer’s pathology itself. The researchers found that astrocytes also influenced the response of microglia, the resident immune cells of the brain, to amyloid plaques. APOE4 astrocytes promoted greater microglial accumulation around plaques and a more disease-associated state, while APOE3 astrocytes were associated with reduced microglial clustering and a more homeostatic profile.
Together, these findings demonstrate that human astrocytes can actively modulate Alzheimer’s disease pathology in an APOE-dependent manner, influencing amyloid and Tau pathology, neuronal damage and the behaviour of other brain cells. The study also highlights the potential of humanized chimeric models to bridge the gap between conventional animal models and human disease by enabling researchers to investigate the specific contribution of human brain cells to neurodegenerative processes in vivo.
The study was led by the Humanized Models of Disease research group at Achucarro Basque Center for Neuroscience and the University of the Basque Country (UPV/EHU), in collaboration with national and international research groups.
Read the full article: https://doi.org/10.1016/j.celrep.2026.117803