Astrocytes and apolipoprotein E (APOE) are both strongly implicated in the pathogenesis and progression of Alzheimer’s disease (AD), yet the impact of astrocytes carrying different APOE variants on key AD hallmarks remains largely unknown. To explore this in a human-relevant context, we generated a chimeric model of AD by transplanting isogenic APOE3 or APOE4 human induced pluripotent stem cell (hiPSC)-derived astrocyte progenitors into the neonatal brains of AD model mice. Six months after transplantation, transplanted cells differentiated into mature astrocytes that predominantly integrate into the upper layers of one cortical hemisphere. Remarkably, APOE3 and APOE4 hAstrocytes differentially affect main AD pathological hallmarks. While APOE3 hAstrocytes ameliorated Aβ pathology, Tau pathology and neuritic dystrophy, APOE4 hAstrocytes aggravated these processes. Moreover, they induced opposing microglial responses to Aβ pathology. APOE4 hAstrocytes enhanced microglia clustering around A β plaques and promoted a disease-associated microglia (DAM)-like transcriptional state. In contrast, APOE3 hAstrocytes reduced clustering and induced a more homeostatic profile. These findings highlight a critical contribution of hAstrocytes to key AD hallmarks in chimeric mice and demonstrate that APOE variant–specific astrocyte functions and APOE isoforms play a pivotal role in AD progression. 

More information:

• https://www.achucarro.org/laboratory/humanized-models-of-disease/