STAT3 ameliorates cognitive deficits by positively regulating the expression of NMDARs in a mouse model of FTDP-17.
Xiao-Yue HongHua-Li WanTing LiBing-Ge ZhangXiao-Guang LiXin WangXiao LiQian LiuChong-Yang ChenYing YangQun WangShu-Peng LiHao YuJian-Zhi WangXi-Fei YangGong-Ping LiuPublished in: Signal transduction and targeted therapy (2020)
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 STAT3flox/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.
Keyphrases
- cell proliferation
- poor prognosis
- mouse model
- endothelial cells
- transcription factor
- type diabetes
- metabolic syndrome
- cerebrospinal fluid
- inflammatory response
- working memory
- room temperature
- immune response
- multiple sclerosis
- insulin resistance
- high glucose
- induced pluripotent stem cells
- white matter
- skeletal muscle
- nuclear factor
- drug induced