PICALM Rescues Endocytic Defects Caused by the Alzheimer’s Disease Risk Factor APOE4
Priyanka Narayan, Grzegorz Sienski, Julia Maeve Bonner, Yuan-Ta Lin, Jinsoo Seo, Valeriya Baru, Aftabul Haque, Blerta Milo, Leyla Anne Akay, Agnese Graziosi, Yelena Freyzon, Dirk Landgraf, William R. Hesse, Julie S. Valastyan, M. Inmaculada Barrasa, Li‐Huei Tsai, Susan Lindquist
Abstract
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.