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Probing the therapeutic potential of TRPC6 for Alzheimer’s disease in live neurons from patient-specific iPSCs
Ran Tao1,† , Rui Lu2,† , Junfeng Wang2 , Shujun Zeng3,4 , Ting Zhang1 , Wenke Guo1,5 , Xiaobing Zhang6 , Qi Cheng3,4 , Chunmei Yue1,* , Yizheng Wang7,* , Naihe Jing1,5,*
1State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China
2Laboratory of Neural Signal Transduction, Institute of Neuroscience, Chinese Academy of Sciences, Shanghai 200031, China
3Department of Neurology, Ruijin Hospital affiliated with the School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, China
4School of Public Health, Shanghai Jiao Tong University, Shanghai 200025, China
5School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
6Division of Regenerative Medicine, Department of Medicine, Loma Linda University, CA 92350, USA
7National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai 200040, China
†These authors contributed equally to the work.
*Correspondence to:Chunmei Yue , Email:cmyue@sibcb.ac.cn Yizheng Wang , Email:yzwang57@sina.com Naihe Jing , Email:njing@sibcb.ac.cn
J Mol Cell Biol, Volume 12, Issue 10, October 2020, 807-816,  https://doi.org/10.1093/jmcb/mjaa027
Keyword: transient receptor potential canonical 6 (TRPC6), Alzheimer’s disease, patient-specific induced pluripotent stem cells (iPSCs), cellular models, amyloid-beta (Aβ)

The induced pluripotent stem cells (iPSCs) offer an unprecedented opportunity to model and study Alzheimer’s disease (AD) under patient-specific genetic background. The lower expression of transient receptor potential canonical 6 (TRPC6) was associated with AD patients, which might be involved in AD pathogenesis. However, the role of TRPC6 that played in AD process still needs more investigation in patient-relevant neurons. In this study, the iPSCs were generated from peripheral blood cells of sporadic AD patients and efficiently differentiated into mature cortical neurons. These sporadic AD-bearing neurons displayed higher levels of AD pathological markers Aβ and phospho-tau, but lower levels of TRPC6, than those of control neurons. Treatment of AD neurons with TRPC6 protein fragment or agonist inhibited the elevation of Aβ and phospho-tau. Our results in live AD neurons manifest that the compromised expression of TRPC6 substantially contributed to Aβ pathology of sporadic AD, suggesting that targeting TRPC6 could help to develop novel therapeutic strategies for the treatments of AD.


Volume 12, Issue 10
October 2020