Since it has been reported that in human apoE3 and apoE4 knock-in (KI) mice expressing human APP with mutations that cause familial AD, apoE4 appears to reduce Aβ clearance and stimulate Aβ deposition in the brain without affecting Aβ production23, we wondered whether the difference in apoE4’s effect on Aβ production between the current human neuron study and the previously reported mouse data reflects species difference in apoE regulation of Aβ metabolism. To address this question, we also generated mouse iPSC (miPSC) lines from human apoE3-KI and apoE4-KI mouse fibroblasts, differentiated them into neurons in culture for 7–8 weeks, and measured Aβ secretion from the miPSC-derived neurons in culture. Clearly, there were no significant differences in both Aβ40 and Aβ42 levels in the culture medium of neurons derived from apoE3/3-miPSC and apoE4/4-miPSC lines (Supplementary Fig. 3). These data indicate the species difference in apoE isoform regulation of Aβ metabolism—apoE4 stimulates Aβ production in human neurons but not in mouse neurons.
