In Vivo Chimeric Alzheimer's Disease Modeling of Apolipoprotein E4 Toxicity in Human Neurons

Despite its clear impact on Alzheimer’s Disease (AD) risk, apolipoprotein (apo) E4’s contributions to AD etiology remain poorly understood. Progress in answering this and other questions in AD research has been limited by an inability to model human-specific phenotypes in an in vivo environment. Here we transplanted human induced pluripotent stem cell derived neurons carrying normal apoE3 or pathogenic apoE4 into human apoE3 or apoE4 knock-in mouse hippocampus, enabling us to disentangle the effects of apoE4 produced in human neurons and in the brain environment. Using single nucleus RNA-sequencing, we identified key transcriptomic differences between human and mouse neurons, as well as transcriptional changes specific to human neuron subtypes, in response to apoE4 . We also found A β from transplanted human neurons formed plaque-like aggregates, with differences in localization and interaction with microglia depending on the transplant and host apoE genotype, again highlighting the power of chimeric modeling for studying AD.