Chunk #17 — RESULTS — Reintroducing different apoE isoforms into apoE-deficient human neurons reveals a gain of toxic effects from apoE4 in hiPSC-derived apoE-null neurons
To determine whether apoE4 induces a loss of function or a gain of toxic effects in human neurons, we also generated a hiPSC line from a subject with apoE deficiency (apoE−/−)30. The apoE−/− hiPSC line had ES cell–like morphology (Supplementary Fig. 9a,b), expressed pluripotency marker genes (Supplementary Fig. 9c–f), and generated neural stem cells (Supplementary Fig. 9g,h) and neurons (Supplementary Fig. 9i). Interestingly, the p-tau levels (Fig. 5a,b and Supplementary Fig. 10a) and the pattern of p-tau immunostaining (Supplementary Fig. 10b–d) in these neurons were similar to those in neurons derived from the isogenic apoE3/3-hiPSCs. ApoE−/− hiPSC-derived neurons and the isogenic apoE3/3-hiPSC-derived neurons secreted similar levels of Aβ40 and Aβ42 into the medium (Fig. 5c,d). Furthermore, apoE−/− hiPSCs and the isogenic apoE3/3-hiPSCs generated similar numbers of GABA-positive neurons (Fig. 5e–g). Thus, the phenotypes of apoE-null neurons were similar to those of apoE3/3 neurons.
