PICALM Rescues Endocytic Defects Caused by the Alzheimer’s Disease Risk Factor APOE4

The ε4 allele of apolipoprotein E (APOE4) is a genetic risk factor for many diseases, including late-onset Alzheimer’s disease (AD). We investigate the cellular consequences of APOE4 in human iPSC-derived astrocytes, observing an endocytic defect in APOE4 astrocytes compared with their isogenic APOE3 counterparts. Given the evolutionarily conserved nature of endocytosis, we built a yeast model to identify genetic modifiers of the endocytic defect associated with APOE4. In yeast, only the expression of APOE4 results in dose-dependent defects in both endocytosis and growth. We discover that increasing expression of the early endocytic adaptor protein Yap1802p, a homolog of the human AD risk factor PICALM, rescues the APOE4-induced endocytic defect. In iPSC-derived human astrocytes, increasing expression of PICALM similarly reverses endocytic disruptions. Our work identifies a functional interaction between two AD genetic risk factors—APOE4 and PICALM—centered on the conserved biological process of endocytosis. [Display omitted] •APOE4 disrupts early endocytic trafficking in iPSC-derived astrocytes•We establish an APOE4 yeast model in which APOE4 affects early endocytic trafficking•Yap1802, the yeast homolog of human PICALM, suppresses endocytic defects in APOE4 yeast•Increasing PICALM expression reverses endocytic defects in APOE4 astrocytes APOE4 is the strongest genetic risk factor for late-onset Alzheimer’s disease (AD). Narayan and Sienski et al. find that APOE4 disrupts early endocytosis, a process by which cells take up external material. By increasing the levels of another AD risk factor, PICALM, the authors are able to reverse these disruptions.