PICALM Rescues Endocytic Defects Caused by the Alzheimer’s Disease Risk Factor APOE4
Priyanka Narayan,
Grzegorz Sienski,
Julia M. Bonner,
Yuan-Ta Lin,
Jinsoo Seo,
Valeriya Baru,
Aftabul Haque,
Blerta Milo,
Leyla A. Akay,
Agnese Graziosi,
Yelena Freyzon,
Dirk Landgraf,
William R. Hesse,
Julie Valastyan,
M. Inmaculada Barrasa,
Li-Huei Tsai,
Susan Lindquist
Affiliations
Priyanka Narayan
Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Genetics and Biochemistry Branch, NIDDK, National Institutes of Health, Bethesda, MD 20814, USA
Grzegorz Sienski
Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA
Julia M. Bonner
Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
Yuan-Ta Lin
Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
Jinsoo Seo
Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
Valeriya Baru
Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA
Aftabul Haque
Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA
Blerta Milo
Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
Leyla A. Akay
Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
Agnese Graziosi
Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
Yelena Freyzon
Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA
Dirk Landgraf
Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA
William R. Hesse
Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA
Julie Valastyan
Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA
M. Inmaculada Barrasa
Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA
Li-Huei Tsai
Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Corresponding author
Susan Lindquist
Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Howard Hughes Medical Institute, Cambridge, MA 02139, USA
Summary: 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.
