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

doi:10.1016/j.celrep.2020.108224

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

Cell Rep. 2020 Oct 6;33(1):108224. doi: 10.1016/j.celrep.2020.108224.

Authors

Priyanka Narayan¹, Grzegorz Sienski², Julia M Bonner³, Yuan-Ta Lin⁴, Jinsoo Seo⁴, Valeriya Baru², Aftabul Haque², Blerta Milo⁴, Leyla A Akay⁴, Agnese Graziosi⁴, Yelena Freyzon², Dirk Landgraf², William R Hesse², Julie Valastyan², M Inmaculada Barrasa², Li-Huei Tsai⁵, Susan Lindquist⁶

Affiliations

¹ 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.
² Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
³ Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
⁴ Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
⁵ 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. Electronic address: lhtsai@mit.edu.
⁶ 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.

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.

Keywords: Alzheimer's disease; PICALM; apolipoprotein E; astrocytes; endocytosis; genetic risk factors; iPS cells; neurodegenerative disease; stem cells; trafficking; yeast.

Publication types

Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't

MeSH terms

Alzheimer Disease / genetics*
Alzheimer Disease / pathology
Apolipoprotein E4 / metabolism*
Endocytosis / physiology*
Humans
Risk Factors

Substances

Apolipoprotein E4

Abstract

Publication types

MeSH terms

Substances

Grants and funding