In humans and transgenic mice, apoE4 is associated with increased Aβ accumulation and amyloid plaque formation in the brain1,40. In apoE3 and apoE4 knock-in mice expressing human APP with mutations that cause familial AD, apoE4 appears to reduce Aβ clearance and stimulate Aβ deposition, especially during the initial seeding stage of plaque formation41,42, in the brain without affecting Aβ production23. We found that the endogenously expressed apoE4 significantly stimulates Aβ production in cultured human neurons, likely by enhancing APP processing. Thus, apoE4’s effects on Aβ production are species specific. Importantly, conversion of apoE4 to apoE3 by gene editing significantly lowered Aβ production, consistent with a specific effect of apoE4. This observation highlights the phenotypic differences between mouse and human cellular models of AD. Those differences must be recognized to understand why so many AD drugs in development failed in human clinical trials, even though they worked beautifully in mouse models of AD, and to develop drugs that are more likely effective in AD patients.
