DIVERGENT EFFECTS OF APOE3 AND APOE4 HUMAN ASTROCYTES ON KEY ALZHEIMER’S DISEASE HALLMARKS IN CHIMERIC MICE

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. Five to six months after transplantation, transplanted cells differentiated into mature astrocytes that predominantly integrate into the upper layers of one cortical hemisphere and adopted morphological features consistent with interlaminar astrocytes (h-iAstrocytes), a population whose role in AD remains unexplored. Remarkably, APOE3 and APOE4 h-iAstrocytes differentially affect main AD pathological hallmarks. While APOE3 h-iAstrocytes ameliorated Aβ pathology, Tau pathology and neuritic dystrophy, APOE4 h-iAstrocytes aggravated these processes. Moreover, they induced opposing microglial responses to Aβ pathology. APOE4 h-iAstrocytes enhanced microglia clustering around Aβ plaques and promoted a disease-associated microglia (DAM)-like transcriptional state. In contrast, APOE3 h-iAstrocytes reduced clustering and induced a more homeostatic profile. These findings highlight a critical contribution of h-iAstrocytes 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.