PICALM Rescues Endocytic Defects Caused by the Alzheimer’s Disease Risk Factor APOE4
Name
1-s2.0-S2211124720312134-main.pdf
Description
Published version
Size
2.63 MB
Format
Adobe PDF
Checksum (MD5)
2749dfad040a3a1d8db02275bfc39f92
Author(s)
Narayan, Priyanka
Sienski, Grzegorz
Bonner, Julia M
Lin, Yuan-Ta
Seo, Jinsoo
Baru, Valeriya
Haque, Aftabul
Milo, Blerta
Akay, Leyla A
Graziosi, Agnese
Date Issued
2020
Journal
Cell Reports
Publisher
Elsevier BV
Version
Final published version
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.
MIT Department
Whitehead Institute for Biomedical Research
Picower Institute for Learning and Memory
Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences
Massachusetts Institute of Technology. Department of Biology
Howard Hughes Medical Institute
Terms of Use
Creative Commons Attribution-NonCommercial-NoDerivs License
Persistent DSpace Link
DOI of Published Version
https://doi.org/10.1016/J.CELREP.2020.108224
