251. STAT3 ameliorates cognitive deficits via regulation of NMDAR expression in an Alzheimer's disease animal model
- Author
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Zai-Hua Zhao, Shi Zhao, Ting Li, Gong-Ping Liu, Xue-Feng Shen, Jian-Zhi Wang, Hua-Li Wan, Qun Wang, Bing-Ge Zhang, Qian Liu, and Xiao-Yue Hong
- Subjects
Male ,STAT3 Transcription Factor ,Medicine (miscellaneous) ,tau Proteins ,Hippocampal formation ,Hippocampus ,Receptors, N-Methyl-D-Aspartate ,STAT3 ,Synapse ,Mice ,Cognition ,synapse ,Alzheimer Disease ,Memory ,medicine ,Animals ,Humans ,Cognitive Dysfunction ,STAT1 ,Phosphorylation ,Pharmacology, Toxicology and Pharmaceutics (miscellaneous) ,Memory Disorders ,Neuronal Plasticity ,biology ,Neurodegeneration ,HEK 293 cells ,medicine.disease ,NMDAR ,Mice, Inbred C57BL ,Disease Models, Animal ,HEK293 Cells ,STAT1 Transcription Factor ,Synapses ,Synaptic plasticity ,biology.protein ,NMDA receptor ,Tau ,memory deficit ,Neuroscience ,Research Paper - 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.
- Published
- 2021