Liang Tao, Hang Weijian, Chen Jiehui, Wu Yue, Wen Bin, Xu Kai, Ding Bingbing, Chen Juan
Department of Biochemistry and Molecular Biology, School of Basic Medicine and the Collaborative Innovation Center for Brain Science, Tongji Medical College, Huazhong University of Science and Technology, 430030, Wuhan, China.
Department of Clinical laboratory, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022, Wuhan, China.
Cell Biosci. 2021 Mar 6;11(1):50. doi: 10.1186/s13578-021-00563-y.
Apolipoprotein E4 (apoE4) is a major genetic risk factor of Alzheimer's disease. Its C-terminal-truncated apoE4 (Δ272-299) has neurotoxicity by affecting mitochondrial respiratory function. However, the molecular mechanism(s) underlying the action of apoE4 (Δ272-299) in mitochondrial function remain poorly understood.
The impact of neuronal apoE4 (Δ272-299) expression on ER stress, mitochondrial-associated membrane (MAM) formation, GRP75, calcium transport and mitochondrial impairment was determined in vivo and in vitro. Furthermore, the importance of ER stress or GRP75 activity in the apoE4 (Δ272-299)-promoted mitochondrial dysfunction in neuron was investigated.
Neuronal apoE4 (Δ272-299) expression induced mitochondrial impairment by inducing ER stress and mitochondrial-associated membrane (MAM) formation in vivo and in vitro. Furthermore, apoE4 (Δ272-299) expression promoted GRP75 expression, mitochondrial dysfunction and calcium transport into the mitochondria in neuron, which were significantly mitigated by treatment with PBA (an inhibitor of ER stress), MKT077 (a specific GRP75 inhibitor) or GRP75 silencing.
ApoE4 (Δ272-299) significantly impaired neuron mitochondrial function by triggering ER stress, up-regulating GRP75 expression to increase MAM formation, and mitochondrial calcium overload. Our findings may provide new insights into the neurotoxicity of apoE4 (Δ272-299) against mitochondrial function and uncover new therapeutic targets for the intervention of Alzheimer's disease.
载脂蛋白E4（apoE4）是阿尔茨海默病的主要遗传风险因素。其C末端截短的apoE4（Δ272 - 299）通过影响线粒体呼吸功能具有神经毒性。然而，apoE4（Δ272 - 299）在线粒体功能中发挥作用的分子机制仍知之甚少。
在体内和体外确定神经元apoE4（Δ272 - 299）表达对内质网应激、线粒体相关膜（MAM）形成、GRP75、钙转运和线粒体损伤的影响。此外，研究了内质网应激或GRP75活性在apoE4（Δ272 - 299）促进神经元线粒体功能障碍中的重要性。
神经元apoE4（Δ272 - 299）表达在体内和体外通过诱导内质网应激和线粒体相关膜（MAM）形成诱导线粒体损伤。此外，apoE4（Δ272 - 299）表达促进神经元中GRP75表达、线粒体功能障碍和钙转运到线粒体中，用PBA（内质网应激抑制剂）、MKT077（特异性GRP75抑制剂）或GRP75沉默处理可显著减轻这些作用。
ApoE4（Δ272 - 299）通过触发内质网应激、上调GRP75表达以增加MAM形成和线粒体钙超载，显著损害神经元线粒体功能。我们的研究结果可能为apoE4（Δ272 - 299）对线粒体功能的神经毒性提供新的见解，并揭示阿尔茨海默病干预的新治疗靶点。
