한빛사 논문
Yuan-Ta Lin1,2,6, Jinsoo Seo1,2,5,6, Fan Gao1, Heather M. Feldman3, Hsin-Lan Wen1, Jay Penney1,2, Hugh P. Cam1,2, Elizabeta Gjoneska1,2, Waseem K. Raja1,2, Jemmie Cheng1,2, Richard Rueda1, Oleg Kritskiy1, Fatema Abdurrob1, Zhuyu Peng1, Blerta Milo1, Chung Jong Yu1,2,4, Sara Elmsaouri1, Dilip Dey1, Tak Ko1, Bruce A. Yankner3, Li-Huei Tsai1,2,7,*
1 Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
2 Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
3 Department of Genetics, Harvard Medical School, Boston, MA 02115, USA
4 Harvard University, John A. Paulson School of Engineering and Applied Sciences, Cambridge, MA 02139, USA
5 Present address: Department of Brain and Cognitive Sciences, DGIST, Daegu 42988, Korea
6 These authors contributed equally
7 Lead Contact
*Corresponding author
Abstract
The apolipoprotein E4 (APOE4) variant is the single greatest genetic risk factor for sporadic Alzheimer’s disease (sAD). However, the cell-type-specific functions of APOE4 in relation to AD pathology remain understudied. Here, we utilize CRISPR/Cas9 and induced pluripotent stem cells (iPSCs) to examine APOE4 effects on human brain cell types. Transcriptional profiling identified hundreds of differentially expressed genes in each cell type, with the most affected involving synaptic function (neurons), lipid metabolism (astrocytes), and immune response (microglia-like cells). APOE4 neurons exhibited increased synapse number and elevated Aβ42 secretion relative to isogenic APOE3 cells while APOE4 astrocytes displayed impaired Aβ uptake and cholesterol accumulation. Notably, APOE4 microglia-like cells exhibited altered morphologies, which correlated with reduced Aβ phagocytosis. Consistently, converting APOE4 to APOE3 in brain cell types from sAD iPSCs was sufficient to attenuate multiple AD-related pathologies. Our study establishes a reference for human cell-type-specific changes associated with the APOE4 variant.
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