Deciphering cell type-specific contributions of APOE4 to amyloid accumulation using iPSC derived neural and glial cells Yuan-Ta Lin1,2, Jinsoo Seo1,2, Fan Gao1, Hsin-Lan Wen1, Elizabeth Gjoneska1,2, Waseem K. Raja1,2, Jemmie Cheng1,2, Richard Rueda1, Sara Elmsaouri1, Dilip Dey1, Tak Ko1 and Li-Huei Tsai1,2 1Picower Institute for Learning and Memory, 2 Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
APOE4 is a major genetic risk for late onset sporadic Alzheimer's disease (AD). Yet, little is known regarding the cell-autonomous effect of APOE4 on the cellular functions of various glial and neural cells that contribute to the development of AD pathology. Here, we used CRISPR/Cas9 genome editing with human induced pluripotent stem cells (iPSCs) homozygous for APOE3 to create isogenic lines homozygous for APOE4. Cerebral organoids generated from APOE4 iPSCs developed more Aβ aggregates and exhibited increased tau phosphorylation after 6 months in culture compared to those from APOE3 organoids. Transcriptional and biochemical analyses reveal that APOE4 variant alters gene transcription and compromises multiple cellular functions of glia and neurons that contribute to amyloid accumulation. Moreover, converting APOE4 to APOE3 attenuated AD-related pathology observed in glia, neurons and organoids derived from sporadic AD iPSCs. Taken together, our findings underscore the multifaceted effects of APOE4 on diverse cellular and molecular phenotypes across multiple brain cell types to dramatically impact the developmental trajectory of AD pathology.