Human interlaminar astrocytes with different APOE variants differentially contribute to Alzheimer’s disease pathology

Abstract

AbstractBackgroundIncreasing evidence for a direct contribution of astrocytes as well as different APOE variants to Alzheimer’s disease (AD) main pathological hallmarks comes from cellular and molecular studies in rodent models. Yet these models cannot fully mimic how human astrocytes affect AD pathology as human and rodent astrocytes differ considerably in morphology, functionality, and gene expression.MethodTo address these challenges, we established an approach to study human astrocytes carrying APOE3 and APOE4 isoforms within the AD brain environment by transplanting human induced pluripotent stem cell (hiPSC)‐derived astrocyte progenitors into neonatal brains of suitable AD model mice.ResultAPOE3 and APOE4 transplanted cells similarly differentiate into astrocytes within the mouse host brain and very often integrate in upper layers of one cortical hemisphere, where they acquire morphological phenotypes resembling human interlaminar astrocytes (h‐ILAs). Interestingly, in AD model mice APOE3 and APOE4 h‐ILAs differentially express and secrete the apoE protein (Figure 1), and differentially affect amyloid‐beta load (Figure 2), microglial responses (Figure 3) and neuritic dystrophy.ConclusionWe describe here a promising model that allows for the first time studying h‐ILAs in the AD brain environment. Importantly, our model reveals a differential contribution of h‐ILAs with different APOE variants to main pathological hallmarks of AD, which can potentially have important implications when developing novel astrocyte‐specific targeting therapeutics.