- Isogenic APOE3 or APOE4 human iPSC‑derived astrocyte progenitors were transplanted into neonatal AD mice and integrated as interlaminar-like human astrocytes.
- APOE3 astrocytes associate differently with Aβ and reduce Aβ burden, Tau pathology, and neuritic dystrophy; APOE4 astrocytes exacerbate these pathologies.
- APOE4 astrocytes promote microglial clustering around Aβ plaques and a disease associated microglia-like state; APOE3 astrocytes reduce clustering and support homeostasis.
Cell Rep. 2026 Aug 8;45(8):117803. doi: 10.1016/j.celrep.2026.117803. Online ahead of print.
ABSTRACT
Astrocytes and APOE are strongly implicated in Alzheimer’s disease (AD), yet the impact of astrocytes carrying different APOE variants on AD hallmarks remains incompletely understood. Here, we generate a chimeric model of AD by transplanting isogenic APOE3 or APOE4 human induced pluripotent stem cell-derived astrocyte progenitors into neonatal AD mice. Donor cells differentiate into human astrocytes that integrate into the cortex and display morphologies consistent with interlaminar-like astrocytes. APOE3 and APOE4 astrocytes differ in expression of APOE, which associates differentially with Aβ plaques. Notably, APOE3 astrocytes are associated with reduced Aβ burden, Tau pathology, and neuritic dystrophy, whereas APOE4 astrocytes exacerbate these processes. They also induce distinct microglial responses: APOE4 astrocytes enhance microglial clustering around Aβ plaques and promote a disease-associated microglia-like state, whereas APOE3 astrocytes reduce clustering and support a more homeostatic profile. These findings highlight a role for human astrocytes and APOE-dependent astrocyte functions in modulating AD-related pathology.
PMID:42570239 | DOI:10.1016/j.celrep.2026.117803
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