We previously reported apoE4 domain interaction (Supplementary Fig. 14a)1,35 and identified small-molecule structure correctors that render apoE4 apoE3-like both structurally and functionally (Supplementary Fig. 14b)36–38. In apoE4/4-hiPSC-derived neurons, treatment with one of the structure correctors, PH002 (Supplementary Fig. 14b)36–38, significantly decreased apoE4 fragment levels (Fig. 6a,b), increased GABAergic neuron numbers (Fig. 6c) and GAD67 levels (Fig. 6d,f), reduced p-tau levels (Fig. 6d,e), and decreased Aβ40 and Aβ42 production/secretion (Fig. 6g,h) in a dose-dependent manner (Fig. 6i–l). Thus, the detrimental effects of apoE4 in hiPSC-derived neurons can be ameliorated by a small molecule apoE4 structure corrector. Importantly, treatment of apoE−/− hiPSC-derived neurons with different concentrations of PH002 did not show any significant effects on Aβ production/secretion, p-tau levels, or GAD67 levels (Supplementary Fig. 14c–f), indicating that the efficacy of PH002 depends on the presence of apoE4.
