LAUSR

The mechanisms of amyloid accumulation in familial Alzheimer's disease (FAD) and sporadic AD (SAD) are controversial. In FAD, mutations in presenilin (PSEN) impair γ‐secretase activity and lead to abnormal amyloid β–protein (Aβ) production, thereby increasing the Aβ42/40 ratio. SAD is postulated to be caused by decreased Aβ clearance of apolipoprotein E4 (APOE4), the strongest risk factor for SAD. However, whether intracellular APOE4 affects Aβ production is unclear. Using APOE3 and APOE4 knock‐in (KI) mouse brain and primary cultured fibroblasts from these mice, in this study, we demonstrated that APOE3 and APOE4 bind to the γ‐secretase complex and isoform‐dependently regulate its activity and Aβ production. We found that Aβ40 levels and γ‐secretase activity were higher in APOE knockout mouse brain than in wild‐type mouse brain. APOE4‐KI fibroblasts had significant lower Aβ levels and γ‐secretase activity but higher Aβ42/40 ratio compared with APOE3‐KI cells, indicating that APOE4‐KI reduces Aβ production by inhibiting γ‐secretase activity. Interestingly, the levels of γ‐secretase complex bound to APOE4 are higher than those bound to APOE3, and the levels of γ‐secretase complex in the brain and fibroblasts of APOE4‐KI mice were higher than those of APOE3‐KI mice. Taken together, our findings demonstrate that intracellular APOE4 inhibits Aβ production, more preferentially inhibits Aβ40 production, and thereby induces an increase in the Aβ42/40 ratio via binding to the γ‐secretase complex. These results suggest a novel mechanism in which intracellular APOE4 contributes to the pathogenesis of SAD by inhibiting γ‐secretase activity.