Theranostics 2021; 11(11):5511-5524. doi:10.7150/thno.56541 This issue Cite

Research Paper

STAT3 ameliorates cognitive deficits via regulation of NMDAR expression in an Alzheimer's disease animal model

Hua-Li Wan1*, Xiao-Yue Hong1*, Zai-Hua Zhao2*, Ting Li1, Bing-Ge Zhang1, Qian Liu1, Qun Wang1, Shi Zhao3, Jian-Zhi Wang1,4, Xue-Feng Shen2✉, Gong-Ping Liu1,4✉

1. Department of Pathophysiology, School of Basic Medicine and the Collaborative Innovation Center for Brain Science, Key Laboratory of Ministry of Education of China and Hubei Province for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
2. Department of Occupational and Environmental Health and the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, No 169 of West Changle Road, Xi'an, Shaanxi, 710032, China.
3. Department of Endocrinology, Wuhan Central Hospital, 26 Shengli Street, Jiang'an District, Wuhan 430014, China.
4. Co-innovation Center of Neuroregeneration, Nantong University, Nantong, JS 226001, China.
*These authors contributed equally to this work.

Citation:
Wan HL, Hong XY, Zhao ZH, Li T, Zhang BG, Liu Q, Wang Q, Zhao S, Wang JZ, Shen XF, Liu GP. STAT3 ameliorates cognitive deficits via regulation of NMDAR expression in an Alzheimer's disease animal model. Theranostics 2021; 11(11):5511-5524. doi:10.7150/thno.56541. https://www.thno.org/v11p5511.htm
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Abstract

Graphic abstract

Background: Abnormal tau accumulation in the brain has a positively correlation with neurodegeneration and memory deterioration, but the mechanism underlying tau-associated synaptic and cognitive impairments remains unclear. Our previous work has found that human full length tau (hTau) accumulation activated signal transducer and activator of transcription-1 (STAT1) to suppress N-methyl-D-aspartate receptors (NMDARs) expression, followed by memory deficits. STAT3 also belongs to STAT protein family and is reported to involve in regulation of synaptic plasticity and cognition. Here, we investigated the role of STAT3 in the cognitive deficits induced by hTau accumulation.

Methods: In vitro studies HEK293 cells were used. EMSA, Luciferase reporter assay, and Immunoprecipitation were applied to detect STAT3 activity. In vivo studies, AAV virus were injected into the hippocampal CA3 region of C57 mice. Western blotting, quantitative real-time polymerase chain reaction, and immunofluorescence were applied to examine the level of synaptic proteins. Electrophysiological analysis, behavioral testing and Golgi impregnation were used to determine synaptic plasticity and memory ability recovery after overexpressing STAT3 or non-acetylated STAT1.

Results: Our results showed that hTau accumulation acetylated STAT1 to retain STAT3 in the cytoplasm by increasing the binding of STAT1 with STAT3, and thus inactivated STAT3. Overexpressing STAT3 or non-acetylated STAT1 ameliorated hTau-induced synaptic loss and memory deficits by increasing the expression of NMDARs.

Conclusions: Taken together, our study indicates that hTau accumulation impaired synaptic plasticity through STAT3 inactivation induced suppression of NMDARs expression, revealing a novel mechanism for hTau-associated synapse and memory deficits.

Keywords: Tau, STAT3, synapse, memory deficit, NMDAR


Citation styles

APA
Wan, H.L., Hong, X.Y., Zhao, Z.H., Li, T., Zhang, B.G., Liu, Q., Wang, Q., Zhao, S., Wang, J.Z., Shen, X.F., Liu, G.P. (2021). STAT3 ameliorates cognitive deficits via regulation of NMDAR expression in an Alzheimer's disease animal model. Theranostics, 11(11), 5511-5524. https://doi.org/10.7150/thno.56541.

ACS
Wan, H.L.; Hong, X.Y.; Zhao, Z.H.; Li, T.; Zhang, B.G.; Liu, Q.; Wang, Q.; Zhao, S.; Wang, J.Z.; Shen, X.F.; Liu, G.P. STAT3 ameliorates cognitive deficits via regulation of NMDAR expression in an Alzheimer's disease animal model. Theranostics 2021, 11 (11), 5511-5524. DOI: 10.7150/thno.56541.

NLM
Wan HL, Hong XY, Zhao ZH, Li T, Zhang BG, Liu Q, Wang Q, Zhao S, Wang JZ, Shen XF, Liu GP. STAT3 ameliorates cognitive deficits via regulation of NMDAR expression in an Alzheimer's disease animal model. Theranostics 2021; 11(11):5511-5524. doi:10.7150/thno.56541. https://www.thno.org/v11p5511.htm

CSE
Wan HL, Hong XY, Zhao ZH, Li T, Zhang BG, Liu Q, Wang Q, Zhao S, Wang JZ, Shen XF, Liu GP. 2021. STAT3 ameliorates cognitive deficits via regulation of NMDAR expression in an Alzheimer's disease animal model. Theranostics. 11(11):5511-5524.

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