Apolipoprotein E regulates lipid metabolism and \u03b1-synuclein pathology in human iPSC-derived cerebral organoids

Jing Zhao,Xue Wang,Yuan Fu,Nilüfer Ertekin-Taner,David A Brafman,Yuka A Martens,Steven G Younkin,Yan W Asmann,Dennis W Dickson,Chia-Chen Liu,Yingxue Ren,Francis Shue,Xianlin Han,Neill R Graff‐Radford ,Zbigniew K Wszołek ,Wenyan Lü ,Mary Dabney Davis ,Fuyao Li,Ziying Xu,Kai Chen,Takahisa Kanekiyo,Meixia Pan,Guojun Bu

doi:10.1007/s00401-021-02361-9

Abstract

APOE4 is a strong genetic risk factor for Alzheimer’s disease and Dementia with Lewy bodies; however, how its expression impacts pathogenic pathways in a human-relevant system is not clear. Here using human iPSC-derived cerebral organoid models, we find that APOE deletion increases α-synuclein (αSyn) accumulation accompanied with synaptic loss, reduction of GBA levels, lipid droplet accumulation and dysregulation of intracellular organelles. These phenotypes are partially rescued by exogenous apoE2 and apoE3, but not apoE4. Lipidomics analysis detects the increased fatty acid utilization and cholesterol ester accumulation in apoE-deficient cerebral organoids. Furthermore, APOE4 cerebral organoids have increased αSyn accumulation compared to those with APOE3. Carrying APOE4 also increases apoE association with Lewy bodies in postmortem brains from patients with Lewy body disease. Our findings reveal the predominant role of apoE in lipid metabolism and αSyn pathology in iPSC-derived cerebral organoids, providing mechanistic insights into how APOE4 drives the risk for synucleinopathies.

Highlights

Introduction α-synuclein encoded by SNCA is a presynaptic membrane-bound protein abundantly expressed in the brain [3, 60]
We confirmed that cerebral organoids from both parental and isogenic lines predominantly showed a dorsal forebrain region specification at Day 30, containing fluid-filled ventricular zone (VZ)-like structure aligned with Sox2-positive neural progenitors and beta-tubulin III (Tuj1)-positive neuroblasts in an outer layer (Fig. 1a)
We found that the amounts of αSyn and phosphorylated αSyn (p-αSyn) significantly increased in the detergent-insoluble SDS fraction of APOE−/− iPSCderived cerebral organoids compared to those from the parent controls (Fig. 1h-k), no significant differences were detected in the detergent soluble RIPA fraction (Fig. 1f-g)

Summary

Introduction

Introduction α-synuclein (αSyn) encoded by SNCA is a presynaptic membrane-bound protein abundantly expressed in the brain [3, 60]. In contrast to the increase of insoluble αSyn accumulation, Aβ42 levels showed a significant decrease in the SDS fraction of APOE−/− cerebral organoids (Supplementary Fig. 2j-m, online resource).

Results

Conclusion