Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA.
Center for Regenerative Medicine, Neuroregeneration Laboratory, Mayo Clinic, Jacksonville, FL, 32224, USA.
Acta Neuropathol. 2021 Nov;142(5):807-825. doi: 10.1007/s00401-021-02361-9. Epub 2021 Aug 28.
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.
APOE4 是阿尔茨海默病和路易体痴呆的强烈遗传风险因素；然而，其表达如何影响人类相关系统中的致病途径尚不清楚。在这里，我们使用人类诱导多能干细胞衍生的大脑类器官模型发现，APOE 缺失会增加 α-突触核蛋白（αSyn）的积累，伴随着突触丧失、GBA 水平降低、脂滴积累和细胞内细胞器的失调。这些表型部分被外源性 apoE2 和 apoE3 挽救，但不能被 apoE4 挽救。脂质组学分析检测到 apoE 缺陷型大脑类器官中脂肪酸利用和胆固醇酯积累增加。此外，与 APOE3 相比，APOE4 大脑类器官中 αSyn 的积累增加。携带 APOE4 还会增加路易体病患者死后大脑中 apoE 与路易体的结合。我们的研究结果揭示了 apoE 在 iPSC 衍生的大脑类器官中的脂质代谢和 αSyn 病理学中的主要作用，为 APOE4 如何驱动突触核蛋白病的风险提供了机制见解。
