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STAT3 ameliorates cognitive deficits by positively regulating the expression of NMDARs in a mouse model of FTDP-17.

ABSTRACT: In tauopathies, memory impairment positively strongly correlates with the amount of abnormal tau aggregates; however, how tau accumulation induces synapse impairment is unclear. Recently, we found that human tau accumulation activated Signal Transduction and Activator of Transcription-1 (STAT1) to inhibit the transcription of synaptic N-methyl-D-aspartate receptors (NMDARs). Here, overexpressing human P301L mutant tau (P301L-hTau) increased the phosphorylated level of Signal Transduction and Activator of Transcription-3 (STAT3) at Tyr705 by JAK2, which would promote STAT3 translocate into the nucleus and activate STAT3. However, STAT3 was found mainly located in the cytoplasm. Further study found that P301L-htau acetylated STAT1 to bind with STAT3 in the cytoplasm, and thus inhibited the nuclear translocation and inactivation of STAT3. Knockdown of STAT3 in STAT3^flox/flox mice mimicked P301L-hTau-induced suppression of NMDARs expression, synaptic and memory impairments. Overexpressing STAT3 rescued P301L-hTau-induced synaptic and cognitive deficits by increasing NMDARs expression. Further study proved that STAT3 positively regulated NMDARs transcription through direct binding to the specific GAS element of NMDARs promoters. These findings indicate that accumulated P301L-hTau inactivating STAT3 to suppress NMDARs expression, revealed a novel mechanism for tau-associated synapse and cognition deficits, and STAT3 will hopefully serve as a potential pharmacological target for tauopathies treatment.

SUBMITTER: Hong XY

PROVIDER: S-EPMC7762755 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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STAT3 ameliorates cognitive deficits by positively regulating the expression of NMDARs in a mouse model of FTDP-17.

Hong Xiao-Yue XY Wan Hua-Li HL Li Ting T Zhang Bing-Ge BG Li Xiao-Guang XG Wang Xin X Li Xiao X Liu Qian Q Chen Chong-Yang CY Yang Ying Y Wang Qun Q Li Shu-Peng SP Yu Hao H Wang Jian-Zhi JZ Yang Xi-Fei XF Liu Gong-Ping GP

Signal transduction and targeted therapy 20201226 1

In tauopathies, memory impairment positively strongly correlates with the amount of abnormal tau aggregates; however, how tau accumulation induces synapse impairment is unclear. Recently, we found that human tau accumulation activated Signal Transduction and Activator of Transcription-1 (STAT1) to inhibit the transcription of synaptic N-methyl-D-aspartate receptors (NMDARs). Here, overexpressing human P301L mutant tau (P301L-hTau) increased the phosphorylated level of Signal Transduction and Act ...[more]

PMID: 33361763

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Project description:Clinical and neuropathological studies have shown that tau pathology better correlates with the severity of dementia than amyloid plaque burden, making tau an attractive target for the cure of Alzheimer's disease. We have explored whether passive immunization with the 12A12 monoclonal antibody (26-36aa of tau protein) could improve the Alzheimer's disease phenotype of two well-established mouse models, Tg2576 and 3xTg mice. 12A12 is a cleavage-specific monoclonal antibody which selectively binds the pathologically relevant neurotoxic NH226-230 fragment (i.e. NH2htau) of tau protein without cross-reacting with its full-length physiological form(s). We found out that intravenous administration of 12A12 monoclonal antibody into symptomatic (6 months old) animals: (i) reaches the hippocampus in its biologically active (antigen-binding competent) form and successfully neutralizes its target; (ii) reduces both pathological tau and amyloid precursor protein/amyloidβ metabolisms involved in early disease-associated synaptic deterioration; (iii) improves episodic-like type of learning/memory skills in hippocampal-based novel object recognition and object place recognition behavioural tasks; (iv) restores the specific up-regulation of the activity-regulated cytoskeleton-associated protein involved in consolidation of experience-dependent synaptic plasticity; (v) relieves the loss of dendritic spine connectivity in pyramidal hippocampal CA1 neurons; (vi) rescues the Alzheimer's disease-related electrophysiological deficits in hippocampal long-term potentiation at the CA3-CA1 synapses; and (vii) mitigates the neuroinflammatory response (reactive gliosis). These findings indicate that the 20-22 kDa NH2-terminal tau fragment is crucial target for Alzheimer's disease therapy and prospect immunotherapy with 12A12 monoclonal antibody as safe (normal tau-preserving), beneficial approach in contrasting the early Amyloidβ-dependent and independent neuropathological and cognitive alterations in affected subjects.

Dataset Information

STAT3 ameliorates cognitive deficits by positively regulating the expression of NMDARs in a mouse model of FTDP-17.

Publications

STAT3 ameliorates cognitive deficits by positively regulating the expression of NMDARs in a mouse model of FTDP-17.

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