Tau accumulation triggers
            <scp>STAT</scp>
            1‐dependent memory deficits by suppressing
            <scp>NMDA</scp>
            receptor expression

Li, Xiaoguang; Hong, Xiao‐Yue; Wang, Yali; Zhang, Shu‐Juan; Zhang, Jun‐Fei; Liu, Yan‐Chao; Sun, Dong-Shen; Feng, Qiong; Ye, Jinwang; Gao, Yuan; Ke, Dan; Wang, Qun; Li, Hong‐lian; Ye, Keqiang; Liu, Gong‐Ping; Wang, Jian‐Zhi

doi:10.15252/embr.201847202

Cited by 53 publications

(64 citation statements)

References 54 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our previous paper reported that hTau accumulation activated tyrosine kinase JAK2, JNK and ERK, which are reported to mediate phosphorylation of the STAT family [24]. Here, we also found that P301L-hTau activated JAK2, JNK and ERK (Additional le 1: Figure S9a, b).…”

Section: Jak2 Kinase Mediates Phosphorylation Of Stat3 At Y705supporting

confidence: 79%

“…Intracellular P301L-hTau accumulation inactivates STAT3 despite the level of phosphorylated STAT3 increases In our previous study, we found that the accumulated htau increased STAT1 activity, while the activity of HNF1, HOX4C, PLAG1, SMUC, VDR, SF-1 and PIT1 decreased remarkably [24]. STAT3 and STAT1 belong to the STAT protein family, and both are reported to be involved in cognitive functions [25][26][27][28][29][30][31][32].…”

Section: Resultsmentioning

confidence: 89%

“…Our previous study showed that tau accumulation activated STAT1 to inhibit NMDARs transcription [24]. STAT1 acetylation inhibited STAT1 entry into the nucleus [46].…”

Section: P301l-htaumentioning

confidence: 98%

See 2 more Smart Citations

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

Liu

Hong

Wan

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

Background In tauopathies, the degree of neurodegeneration and memory impairment positively strongly correlates with the amount of abnormal tau aggregates. Recently, we found that human wild-type tau accumulation activated Signal Transduction and Activator of Transcription-1 (STAT1) to inhibit the transcription of genes coding for synaptic N-methyl-D-aspartate receptors (NMDARs). STAT3 has similar specific DNA binding element GAS as STAT1, however, the role of STAT3 in cognitive deficits induced by tau accumulation has not reported until now.Methods The activity of the transcription factor was analyzed by luciferase reporter assay or electrophoresis mobility shift assay. AAV virus (AAV-Cre, AAV-P301L, AAV-STAT3 or AAV-K410/3R-STAT1) was infused stereotaxically into the hippocampal CA3 regions of STAT3flox/flox or C57 mice. The spatial learning and memory of the animals were assessed by Morris water maze, the contextual fear conditioning and new object recognition test. The synaptic plasticity was measured by electrophysiological recording and the spine density was detected by Golgi staining. RT-PCR and Western blotting were used to detect the mRNA and protein levels.Results We found that P301L-hTau accumulation acetylated STAT1 at lysine 410 and 413 sites to bind with STAT3 in the cytoplasm which inhibited the nuclear translocation and inactivated STAT3, though phosphorylation of STAT3 at Tyr705, which leads to STAT3 nuclear translocation and DNA binding, increased. Knockdown of STAT3 by AAV-Cre 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 revealed that STAT3 positively regulated NMDARs transcription through direct binding to the specific GAS element of NMDAR1, NMDAR2A and NMDAR2B promoters.Conclusion These findings indicate that accumulated P301L-hTau impairs synaptic plasticity by inactivating STAT3 to suppress NMDARs expression, thereby revealing a novel mechanism for P301L-hTau-associated synapse and cognition deficits.

show abstract

Section: Jak2 Kinase Mediates Phosphorylation Of Stat3 At Y705supporting

confidence: 79%

Section: Resultsmentioning

confidence: 89%

See 1 more Smart Citation

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

Liu

Hong

Wan

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…Given that many kinases can be activated by Ca 2+ , dysregulation of Ca 2+ homeostasis, such as seen during ER stress, can increase tau phosphorylation [14,72,73]. Conversely, intracellular tau accumulating can also induce ER stress and cause Ca 2+ overload, the latter induces dephosphorylation of Ca 2+ -calmodulin-dependent protein kinase IV (CaMKIV) and cAMP-responsive element binding protein (CREB) by activating calcineurin [5]; the Ca 2+ overload can also activate JAK2-STAT1 signaling, and the upregulated STAT1 directly binds to the specific GAS elements of N-methyl-D-aspartate receptors (NMDARs) and thus inhibits the transcription of NMDARs [14]; the cleaved tau-induced STAT1 elevation also activates BACE1 to promote Aβ production [74]; all of which reveal new mechanisms underlying tau-induced synapse impairments and cognitive deficits.…”

Section: Calciummentioning

confidence: 99%

“…[5][6][7]. Recent studies suggest that tau hyperphosphorylation may play a dual role in AD neurodegeneration, i.e., tau hyperphosphorylation renders the cells more resistant to acute apoptosis [8][9][10][11][12], while the increasing intracellular tau accumulation induces multiple cellular impairments, including endoplasmic reticulum (ER) stress, deficits of mitophagy and autophagy, deficits of synaptic transmission, etc., and eventually leads to a chronic neurodegeneration [5,13,14].…”

Section: Introductionmentioning

confidence: 99%

Current understanding of metal ions in the pathogenesis of Alzheimer’s disease

Wang

Yin

Liu

et al. 2020

Transl Neurodegener

295

188

View full text Add to dashboard Cite

Background: The homeostasis of metal ions, such as iron, copper, zinc and calcium, in the brain is crucial for maintaining normal physiological functions. Studies have shown that imbalance of these metal ions in the brain is closely related to the onset and progression of Alzheimer's disease (AD), the most common neurodegenerative disorder in the elderly. Main body: Erroneous deposition/distribution of the metal ions in different brain regions induces oxidative stress. The metal ions imbalance and oxidative stress together or independently promote amyloid-β (Aβ) overproduction by activating βor γ-secretases and inhibiting α-secretase, it also causes tau hyperphosphorylation by activating protein kinases, such as glycogen synthase kinase-3β (GSK-3β), cyclin-dependent protein kinase-5 (CDK5), mitogenactivated protein kinases (MAPKs), etc., and inhibiting protein phosphatase 2A (PP2A). The metal ions imbalances can also directly or indirectly disrupt organelles, causing endoplasmic reticulum (ER) stress; mitochondrial and autophagic dysfunctions, which can cause or aggravate Aβ and tau aggregation/accumulation, and impair synaptic functions. Even worse, the metal ions imbalance-induced alterations can reversely exacerbate metal ions misdistribution and deposition. The vicious cycles between metal ions imbalances and Aβ/tau abnormalities will eventually lead to a chronic neurodegeneration and cognitive deficits, such as seen in AD patients. Conclusion: The metal ions imbalance induces Aβ and tau pathologies by directly or indirectly affecting multiple cellular/ subcellular pathways, and the disrupted homeostasis can reversely aggravate the abnormalities of metal ions transportation/ deposition. Therefore, adjusting metal balance by supplementing or chelating the metal ions may be potential in ameliorating AD pathologies, which provides new research directions for AD treatment.

show abstract

P301S‐hTau acetylates KEAP1 to trigger synaptic toxicity via inhibiting NRF2/ARE pathway: A novel mechanism underlying hTau‐induced synaptic toxicities

Xie

Zhang

et al. 2022

Clinical & Translational Med

Self Cite

View full text Add to dashboard Cite

Background Human Tau (hTau) accumulation and synapse loss are two pathological hallmarks of tauopathies. However, whether and how hTau exerts toxic effects on synapses remain elusive. Methods Mutated hTau (P301S) was overexpressed in the N2a cell line, primary hippocampal neurons and hippocampal CA3. Western blotting and quantitative polymerase chain reaction were applied to examine the protein and mRNA levels of synaptic proteins. The protein interaction was tested by co‐immunoprecipitation and proximity ligation assays. Memory and emotion status were evaluated by a series of behavioural tests. The transcriptional activity of nuclear factor‐erythroid 2–related factor 2 (NRF2) was detected by dual luciferase reporter assay. Electrophoresis mobility shift assay and chromosome immunoprecipitation were conducted to examine the combination of NRF2 to specific anti‐oxidative response element (ARE) sequences. Neuronal morphology was analysed after Golgi staining. Results Overexpressing P301S decreased the protein levels of post‐synaptic density protein 93 (PSD93), PSD95 and synapsin 1 (SYN1). Simultaneously, NRF2 was decreased, whereas Kelch‐like ECH‐associated protein 1 (KEAP1) was elevated. Further, we found that NRF2 could bind to the specific AREs of DLG2, DLG4 and SYN1 genes, which encode PSD93, PSD95 and SYN1, respectively, to promote their expression. Overexpressing NRF2 ameliorated P301S‐reduced synaptic proteins and synapse. By means of acetylation at K312, P301S increased the protein level of KEAP1 via inhibiting KEAP1 degradation from ubiquitin–proteasome pathway, thereby decreasing NRF2 and reducing synapse. Blocking the P301S–KEAP1 interaction at K312 rescued the P301S‐suppressed expression of synaptic proteins and memory deficits with anxiety efficiently. Conclusions P301S‐hTau could acetylate KEAP1 to trigger synaptic toxicity via inhibiting the NRF2/ARE pathway. These findings provide a novel and potential target for the therapeutic intervention of tauopathies.

show abstract

Tau accumulation triggers STAT 1‐dependent memory deficits by suppressing NMDA receptor expression

Cited by 53 publications

References 54 publications

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

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

Current understanding of metal ions in the pathogenesis of Alzheimer’s disease

P301S‐hTau acetylates KEAP1 to trigger synaptic toxicity via inhibiting NRF2/ARE pathway: A novel mechanism underlying hTau‐induced synaptic toxicities

Contact Info

Product

Resources

About