Tau accumulation triggers STAT1‐dependent memory deficits by suppressing NMDA receptor expression
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Abstract
Intracellular tau accumulation forming neurofibrillary tangles is hallmark pathology of Alzheimer's disease (AD), but how tau accumulation induces synapse impairment is elusive. By overexpressing human full-length wild-type tau (termed hTau) to mimic tau abnormality as seen in the brain of sporadic AD patients, we find that hTau accumulation activates JAK2 to phosphorylate STAT1 (signal transducer and activator of transcription 1) at Tyr701 leading to STAT1 dimerization, nuclear translocation, and its activation. STAT1 activation suppresses expression of N-methyl-D-aspartate receptors (NMDARs) through direct binding to the specific GAS element of GluN1, GluN2A, and GluN2B promoters, while knockdown of STAT1 by AAV-Cre in STAT1 flox/flox mice or expressing dominant negative Y701F-STAT1 efficiently rescues hTau-induced suppression of NMDAR expression with amelioration of synaptic functions and memory performance. These findings indicate that hTau accumulation impairs synaptic plasticity through JAK2/STAT1-induced suppression of NMDAR expression, revealing a novel mechanism for hTau-associated synapse and memory deficits.
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In a transgenic mouse model expressing human tau, cognitive impairment is ameliorated when STAT1 signaling is blocked.
“in a transgenic mouse model expressing human tau, cognitive impairment is ameliorated when STAT1 signaling is blocked.”
From Interferon signaling modulates Down syndrome-associated Alzheimer’s disease pathology in a mouse model (2025) · cites this paper as [94]
The Results (‘Downregulating STAT1 rescues hTau-induced memory and synaptic deficits,’ p. 19) report improved learning and memory after STAT1 knockdown in mice expressing human tau. But human tau was introduced by hippocampal AAV injection into STAT1-floxed mice; the cited rescue experiment was not conducted in a transgenic mouse model expressing human tau. (LLM, conf=0.87)
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Cleveland, D. W., Hwo, S.-Y., & Kirschner, M. W. (1977) · Journal of Molecular Biology · doi:10.1016/0022-2836(77)90213-3 · Cited by 915 · see citing works
Tau reduction prevents Aβ-induced axonal transport deficits by blocking activation of GSK3β
Vossel, K. A., Xu, J. C., Fomenko, V., Miyamoto, T., Suberbielle, E., Knox, J. A., Ho, K., Kim, D. H., Yu, G.-Q., & Mucke, L. (2015) · Journal of Cell Biology · doi:10.1083/jcb.201407065 · Cited by 167 · see citing works
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- Arai H, Lee VM, Otvos L, Jr., Greenberg BD, Lowery DE, Sharma SK et al. Defined neurofilament, hTau, and beta-amyloid precursor protein epitopes distinguish Alzheimer from non-Alzheimer senile plaques. Proceedings of the National Academy of Sciences of the United States of America 1990; 87(6): 2249-2253.
- Braak H, Braak E. Demonstration of amyloid deposits and neurofibrillary changes in whole brain sections. Brain pathology 1991; 1(3): 213-216.
- Thal DR, Holzer M, Rub U, Waldmann G, Gunzel S, Zedlick D et al. Alzheimer-related hTau-pathology in the perforant path target zone and in the hippocampal stratum oriens and radiatum correlates with onset and degree of dementia. Experimental neurology 2000; 163(1): 98-110.
- Yin Y, Gao D, Wang Y, Wang ZH, Wang X, Ye J et al. Tau accumulation induces synaptic impairment and memory deficit by calcineurin-mediated inactivation of nuclear CaMKIV/CREB signaling. Proceedings of the National Academy of Sciences of the United States of America 2016; 113(26): E3773-3781.
- Hu YY, He SS, Wang X, Duan QH, Grundke-Iqbal I, Iqbal K et al. Levels of nonphosphorylated and phosphorylated hTau in cerebrospinal fluid of Alzheimer's disease patients : an ultrasensitive bienzyme-substrate-recycle enzyme-linked immunosorbent assay. The American journal of pathology 2002; 160(4): 1269-1278.
- Lin YT, Cheng JT, Yao YC, Juo, Lo YK, Lin CH et al. Increased total TAU but not amyloid-beta(42) in cerebrospinal fluid correlates with short-term memory impairment in Alzheimer's disease. Journal of Alzheimer's disease : JAD 2009; 18(4): 907-918.
- Kelleher I, Garwood C, Hanger DP, Anderton BH, Noble W. Kinase activities increase 31, Li et al. during the development of hTauopathy in hTau mice. Journal of neurochemistry 2007; 103(6): 2256-2267.
- Kimura T, Yamashita S, Fukuda T, Park JM, Murayama M, Mizoroki T et al. Hyperphosphorylated hTau in parahippocampal cortex impairs place learning in aged mice expressing wild-type human hTau. The EMBO journal 2007; 26(24): 5143-5152.
- Rapoport M, Dawson HN, Binder LI, Vitek MP, Ferreira A. Tau is essential to beta - amyloid-induced neurotoxicity. Proceedings of the National Academy of Sciences of the United States of America 2002; 99(9): 6364-6369.
- Roberson ED, Scearce-Levie K, Palop JJ, Yan F, Cheng IH, Wu T et al. Reducing endogenous hTau ameliorates amyloid beta-induced deficits in an Alzheimer's disease mouse model. Science 2007; 316(5825): 750-754.
- Weingarten MD, Lockwood AH, Hwo SY, Kirschner MW. A protein factor essential for microtubule assembly. Proceedings of the National Academy of Sciences of the United States of America 1975; 72(5): 1858-1862.
- Alonso AC, Zaidi T, Grundke-Iqbal I, Iqbal K. Role of abnormally phosphorylated hTau in the breakdown of microtubules in Alzheimer disease. Proceedings of the National Academy of Sciences of the United States of America 1994; 91(12): 5562-5566.
- certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 32, Li et al. 15. Ebneth A, Godemann R, Stamer K, Illenberger S, Trinczek B, Mandelkow E. Overexpression of hTau protein inhibits kinesin-dependent trafficking of vesicles, mitochondria, and endoplasmic reticulum: implications for Alzheimer's disease. The Journal of cell biology 1998; 143(3): 777-794.
- Kunzi V, Glatzel M, Nakano MY, Greber UF, Van Leuven F, Aguzzi A. Unhampered prion neuroinvasion despite impaired fast axonal transport in transgenic mice overexpressing four- repeat hTau. The Journal of neuroscience : the official journal of the Society for Neuroscience 2002; 22(17): 7471-7477.
- Audouard E, Van Hees L, Suain V, Yilmaz Z, Poncelet L, Leroy K et al. Motor deficit in a hTauopathy model is induced by disturbances of axonal transport leading to dying-back degeneration and denervation of neuromuscular junctions. The American journal of pathology 2015; 185(10): 2685-2697.
- Cox K, Combs B, Abdelmesih B, Morfini G, Brady ST, Kanaan NM. Analysis of isoform- specific hTau aggregates suggests a common toxic mechanism involving similar pathological conformations and axonal transport inhibition. Neurobiology of aging 2016; 47: 113-126.
- Li HL, Wang HH, Liu SJ, Deng YQ, Zhang YJ, Tian Q et al. Phosphorylation of hTau antagonizes apoptosis by stabilizing beta-catenin, a mechanism involved in Alzheimer's neurodegeneration. Proceedings of the National Academy of Sciences of the United States of America 2007; 104(9): 3591-3596.
- Duan DX, Chai GS, Ni ZF, Hu Y, Luo Y, Cheng XS et al. Phosphorylation of hTau by death-associated protein kinase 1 antagonizes the kinase-induced cell apoptosis. Journal of Alzheimer's disease : JAD 2013; 37(4): 795-808. 33, Li et al. 21. Luo DJ, Feng Q, Wang ZH, Sun DS, Wang Q, Wang JZ et al. Knockdown of phosphotyrosyl phosphatase activator induces apoptosis via mitochondrial pathway and the attenuation by simultaneous hTau hyperphosphorylation. Journal of neurochemistry 2014; 130(6): 816-825.
- Binder LI, Frankfurter A, Rebhun LI. The distribution of hTau in the mammalian central nervous system. The Journal of cell biology 1985; 101(4): 1371-1378.
- Zhao X, Kotilinek LA, Smith B, Hlynialuk C, Zahs K, Ramsden M et al. Caspase-2 cleavage of hTau reversibly impairs memory. Nature medicine 2016; 22(11): 1268-1276.
- Thies E, Mandelkow EM. Missorting of hTau in neurons causes degeneration of synapses that can be rescued by the kinase MARK2/Par-1. The Journal of neuroscience : the official journal of the Society for Neuroscience 2007; 27(11): 2896-2907.
- Ittner LM, Ke YD, Delerue F, Bi M, Gladbach A, van Eersel J et al. Dendritic function of hTau mediates amyloid-beta toxicity in Alzheimer's disease mouse models. Cell 2010; 142(3): 387-397.
- Hu Y, Li XC, Wang ZH, Luo Y, Zhang X, Liu XP et al. Tau accumulation impairs mitophagy via increasing mitochondrial membrane potential and reducing mitochondrial Parkin. Oncotarget 2016; 7(14): 17356-17368.
- Li XC, Hu Y, Wang ZH, Luo Y, Zhang Y, Liu XP et al. Human wild-type full-length hTau accumulation disrupts mitochondrial dynamics and the functions via increasing mitofusins. Scientific reports 2016; 6: 24756.
- Morris RG, Garrud P, Rawlins JN, O'Keefe J. Place navigation impaired in rats with hippocampal lesions. Nature 1982; 297(5868): 681-683.
- Jiang X, Chai GS, Wang ZH, Hu Y, Li XG, Ma ZW et al. CaMKII-dependent dendrite certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprint (which was not this version posted October 8, 2018. ; https://doi.org/10.1101/437814 doi: bioRxiv preprint 34, Li et al. ramification and spine generation promote spatial training-induced memory improvement in a rat model of sporadic Alzheimer's disease. Neurobiology of aging 2015; 36(2): 867-876. · DOI
- Etherton, M., Foldy, C., Sharma, M., Tabuchi, K., Liu, X., Shamloo, M., Malenka, R.C., and Sudhof, T.C. (2011). Autism-linked neuroligin-3 R451C mutation differentially alters hippocampal and cortical synaptic function. Proceedings of the National Academy of Sciences of the United States of America 108, 13764-13769.
- Koshelnick Y, Ehart M, Hufnagl P, Heinrich PC, Binder BR. Urokinase receptor is associated with the components of the JAK1/STAT1 signaling pathway and leads to activation of this pathway upon receptor clustering in the human kidney epithelial tumor cell line TCL-598. The Journal of biological chemistry 1997; 272(45): 28563-28567.
- Hsu WL, Ma YL, Hsieh DY, Liu YC, Lee EH. STAT1 negatively regulates spatial memory formation and mediates the memory-impairing effect of Abeta. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 2014; 39(3): 746-758.
- Tai DJ, Hsu WL, Liu YC, Ma YL, Lee EH. Novel role and mechanism of protein inhibitor of activated STAT1 in spatial learning. The EMBO journal 2011; 30(1): 205-220.
- Sandelin A, Alkema W, Engstrom P, Wasserman WW, Lenhard B. JASPAR: an open- access database for eukaryotic transcription factor binding profiles. Nucleic acids research certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprint (which was not this version posted October 8, 2018. ; https://doi.org/10.1101/437814 doi: bioRxiv preprint 35, Li et al. 2004; 32(Database issue): D91-94. · DOI
- Liddle FJ, Alvarez JV, Poli V, Frank DA. Tyrosine phosphorylation is required for functional activation of disulfide-containing constitutively active STAT mutants. Biochemistry 2006; 45(17): 5599-5605.
- Zhang Y, Cho YY, Petersen BL, Zhu F, Dong Z. Evidence of STAT1 phosphorylation modulated by MAPKs, MEK1 and MSK1. Carcinogenesis 2004; 25(7): 1165-1175.
- Quelle FW, Thierfelder W, Witthuhn BA, Tang B, Cohen S, Ihle JN. Phosphorylation and activation of the DNA binding activity of purified Stat1 by the Janus protein-tyrosine kinases and the epidermal growth factor receptor. The Journal of biological chemistry 1995; 270(35): 20775-20780.
- Darnell JE, Jr. STATs and gene regulation. Science 1997; 277(5332): 1630-1635.
- Jatiani SS, Baker SJ, Silverman LR, Reddy EP. Jak/STAT pathways in cytokine signaling and myeloproliferative disorders: approaches for targeted therapies. Genes & cancer 2010; 1(10): 979-993.
- Wegenka UM, Buschmann J, Lutticken C, Heinrich PC, Horn F. Acute-phase response factor, a nuclear factor binding to acute-phase response elements, is rapidly activated by interleukin-6 at the posttranslational level. Molecular and cellular biology 1993; 13(1): 276- 288.
- Sadowski HB, Shuai K, Darnell JE, Jr., Gilman MZ. A common nuclear signal transduction pathway activated by growth factor and cytokine receptors. Science 1993; 261(5129): 1739- 1744.
- Sharma B, Iozzo RV. Transcriptional silencing of perlecan gene expression by interferon- gamma. The Journal of biological chemistry 1998; 273(8): 4642-4646. 36, Li et al. 44. Shuai K, Liu B. Regulation of JAK-STAT signalling in the immune system. Nature reviews Immunology 2003; 3(11): 900-911.
- Echeverria V, Yarkov A, Aliev G. Positive modulators of the alpha7 nicotinic receptor against neuroinflammation and cognitive impairment in Alzheimer's disease. Progress in neurobiology 2016; 144: 142-157.
- Baruch K, Rosenzweig N, Kertser A, Deczkowska A, Sharif AM, Spinrad A et al. Breaking immune tolerance by targeting Foxp3(+) regulatory T cells mitigates Alzheimer's disease pathology. Nature communications 2015; 6: 7967.
- Lee YJ, Choi DY, Choi IS, Kim KH, Kim YH, Kim HM et al. Inhibitory effect of 4-O- methylhonokiol on lipopolysaccharide-induced neuroinflammation, amyloidogenesis and memory impairment via inhibition of nuclear factor-kappaB in vitro and in vivo models. Journal of neuroinflammation 2012; 9: 35.
- certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.
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“…JAK/STAT1 signaling, it was previously shown that accumulated tau impairs synaptic function and memory performance as a result of activated JAK2/STAT1 signaling (Li et al., 2019), an effect that could potentially be exacerbated further by microglia- mediated IL- 27/JAK/STAT1 signaling in neurons.”
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Self-citationJiang, X. J., Wu, Y. Q., Ma, R., Chang, Y. M., Li, L. L., Zhu, J. H., Liu, G. P., & Li, G. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.736267 · Cited by 22 · see citing works
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Self-citationWu, D., Yu, N., Gao, Y., Xiong, R., Liu, L., Lei, H., Jin, S., Liu, J., Liu, Y., Xie, J., et al. (2023) · Molecular Neurodegeneration · doi:10.1186/s13024-023-00614-7 · Cited by 17 · see citing works
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“The experiments of IHC and IF were performed using the established protocol [30].”
Self-citationHu, L.-Q., Liu, Y., Yuan, Z., Guo, H., Duan, R., Ke, P., Meng, Y., Tian, X., & Xiao, F. (2024) · Redox Biology · doi:10.1016/j.redox.2024.103236 · Cited by 13 · see citing works
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Self-citationMa, D., Luo, Y., Huang, R., Zhao, Z., Zhang, L., Li, Y., Wang, Q., Li, L., & Zhang, L. (2020) · Current Medical Science · doi:10.1007/s11596-020-2284-z · Cited by 15 · see citing works
Self-citationWang, X., Liu, E.-J., Liu, Q. R., Li, S., Li, T., Zhou, Q., Liu, Y., Zhang, H., & Wang, J. (2020) · Journal of Alzheimer s Disease · doi:10.3233/jad-200529 · Cited by 16 · see citing works
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Self-citationMa, D., Huang, R., Guo, K., Zhao, Z., Wei, W., Gu, L.-H., Li, L., & Zhang, L. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.671206 · Cited by 13 · see citing works
“Cornel Iridoid Glycoside Treatment Inhibited the Janus Kinase-2/Signal Transducer and Activator of Transcription 1 Pathway in the Cerebral Cortex of P301S Mice JAK2/STAT1 signaling pathway was reported to be involved with the decreased expression of NMDARs induced by tau pathology (Li et al., 2019).”
BackgroundInfluentialChang, Y., Yao, Y., Ma, R., Wang, Z., Hu, J., Wu, Y., Jiang, X., Li, L., & Li, G. (2021) · Frontiers in Neuroscience · doi:10.3389/fnins.2021.620176 · Cited by 13 · see citing works
“…the protein levels of well-established synaptic markers, including the NMDAR obligatory subunit NR2B, the AMPAR subunit GluR1 (Huganir and Nicoll, 2013; Diering and Huganir, 2018; Li et al., 2019), and PSD95 in the hippocampi (Hoover et al., 2010; Sydow et al., 2011) using western blotting.”
MethodT217-Phosphorylation Exacerbates Tau Pathologies and Tau-Induced Cognitive Impairment
Wang, X., Liu, Q. R., Li, X., Zhou, Q., Wu, D., Li, S., Liu, Y., & Wang, J. (2021) · Journal of Alzheimer s Disease · doi:10.3233/jad-210297 · Cited by 17 · see citing works
Self-citation4R Tau Modulates Cocaine-Associated Memory through Adult Dorsal Hippocampal Neurogenesis
Li, H., Xu, W., Wang, D., Wang, L., Fang, Q., Wan, X., Zhang, J., Hu, Y., Li, H., Zhang, J., et al. (2021) · Journal of Neuroscience · doi:10.1523/jneurosci.2848-20.2021 · Cited by 13 · see citing works
“Tau accumulation plays an important role in memory impairment (Yin et al., 2016; Li et al., 2019), and a decrease in Tau expression prevents neuronal loss, amyloid b -induced axonal transport deficits as well as memory impairment in tauopathy models (Vossel et al., 2010, 2015; DeVos et al., 2017).”
BackgroundSelf-citationTau Acts in Concert With Kinase/Phosphatase Underlying Synaptic Dysfunction
Fan, X., Xia, L., Zhou, Z., Qiu, Y., Zhao, C., Yin, X., & Qian, W. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2022.908881 · Cited by 11 · see citing works
Anschuetz, A., Schwab, K., Harrington, C. R., Wischik, C. M., & Riedel, G. (2025) · Journal of Alzheimer s Disease · doi:10.1177/13872877251362212 · Cited by 7 · see citing works
Role of Mitochondrial Calcium Dysregulation in Alzheimer’s Disease Pathogenesis
Ebrahimi, R., Hatami, S., Hashempoor, A., Oraee, S., Salarvandian, S., Faramarzi, A., & Esmaeilpour, K. (2025) · Molecular Neurobiology · doi:10.1007/s12035-025-05465-5 · Cited by 8 · see citing works
“Calcium influences the processing of APP, promoting increased production of Aβ [73] and the formation of NFTs [74, 75].”
MBD5 regulates NMDA receptor expression and seizures by inhibiting Stat1 transcription
Tang, F.-L., Zhang, X., Ke, P., Liu, J., Zhang, Z., Hu, D., Gu, J., Zhang, H., Guo, H., Zang, Q.-W., et al. (2023) · Neurobiology of Disease · doi:10.1016/j.nbd.2023.106103 · Cited by 8 · see citing works
“Consistent with the recognized role of NMDARs in epilepsy and the previously reported effect of STAT1 on the expression of NMDARs (Li et al., 2019), we found increased expression of GluN1, GluN2A and GluN2B in mice treated with exogenous MBD5.”
BackgroundInfluentialZhang, J., Li, X., Xiao, J. F., Xiang, Y., & Ye, F. (2023) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2023.1072184 · Cited by 7 · see citing works
Self-citationAraya, P., Niemeyer, B., Schade, K., Dunn, L. N., Waugh, K., Busquet, N., Brindley, C., Brown, C., Winkler, C., Lyford, H. R., et al. (2025) · iScience · doi:10.1016/j.isci.2025.113130 · Cited by 7 · see citing works
“94 Consistent with a recent study that demonstrated that genes on HSA21 decreased A β accumulation in the brain of 8-month-old DS-AD mice, 62 we found decreased A β levels in the cortex, with trends toward decreased levels throughout the brain.”
STAT3 ameliorates truncated tau-induced cognitive deficits
Zhang, B., Wan, H., Maierwufu, M., Liu, Q., Li, T., He, Y., Wang, X., Liu, G., Hong, X., & Feng, Q. (2023) · Neural Regeneration Research · doi:10.4103/1673-5374.382253 · Cited by 8 · see citing works
“Our recent studies found that STAT3 positively regulates NMDAR transcription by directly binding with specific gamma interferon activation site (GAS) elements in the promoters of GluN1, GluN2A, or GluN2B (Li et al., 2019; Hong et al., 2020; Wan et al., 2021).”
InfluentialSelf-citationZhu, J., Jiang, X., Chang, Y., Wu, Y., Sun, S., Wang, C., Zheng, S., Wang, M., Yao, Y., Li, G., et al. (2023) · International Immunopharmacology · doi:10.1016/j.intimp.2023.110649 · Cited by 9 · see citing works
Advances in Alzheimer’s disease: mechanistic insights and therapeutic targets
Jia, Y.-J., Ge, Y., Li, B., Yang, Y., Chen, H., Liu, J., Guo, J., Yu, J., Ye, K., Wang, J., et al. (2026) · Science China Life Sciences · doi:10.1007/s11427-025-2991-7 · Cited by 5 · see citing works
“Moreover, evidence suggests that tau can reduce the expression of synapse-associated proteins with the mechanisms involving calcineurin-CREB and signal transduction and activator of transcription-1/3 (STAT1/3) signaling, leading to impaired cognitive functions (Li et al., 2019; Wan et al., 2021).”
Self-citationShao, X., Sun, J., Wang, X. B., Yin, X., Chen, Z., Xu, Y., Wang, T., Yuan, B., Qiu, W., Liu, F., et al. (2025) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.5c00475 · Cited by 6 · see citing works
Song, Y., Ni, J., Qing, H., & Quan, Z. (2025) · Translational Neurodegeneration · doi:10.1186/s40035-025-00511-7 · Cited by 5 · see citing works
“Conditional knockout of STAT1 using AAV-Cre or expression of dominant-negative Y701F-STAT1 rescues the hTau-induced suppression of NMDAR expression and improves synaptic function and memory in mice [158].”
STATs, promising targets for the treatment of autoimmune and inflammatory diseases
He, X., Liu, P., Luo, Y., Fu, X.-Y., & Yang, T. (2024) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2024.116783 · Cited by 5 · see citing works
SGLT2 Inhibitors in Alzheimer’s Disease: Biochemical Insights and Therapeutic Potential
Mazzeo, P., Vietri, M., Tecce, N., Delizia, A., Remondelli, V., Ciaglia, T., Dio, A. D., Corletti, L., Pizzuti, C. G., Pepe, G., et al. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27115051 · Cited by 2 · see citing works
“Treatment of RAW 264.7 macrophages with increasing concentrations of em-pagliflozin significantly inhibited mRNA expression of inflammatory mediators, indicating a direct inhibitory effect on JAK2/STAT1-dependent transcriptional activity [153,154].”
InfluentialCalbindin-D28k deficiency mediates tau-driven hippocampal hyperexcitement and cognitive impairment
Gao, Y., Tao, X., Wang, Y., Wang, Y., Li, H., Yu, Y., Tu, M., Liu, Y., Zhou, J., Li, Y., et al. (2026) · Translational Neurodegeneration · doi:10.1186/s40035-026-00547-3 · Cited by 2 · see citing works
Self-citationDuboëlle, M., Lercara, A., Pers, Y., Michel, C., Lepelley, M., Valnet‐Rabier, M., Faillie, J., Brès, V., & Palassin, P. (2026) · Fundamental and Clinical Pharmacology · doi:10.1111/fcp.70072 · Cited by 2 · see citing works
Galindez, G., López, B., Blumenthal, D., & Kacprowski, T. (2024) · bioRxiv · doi:10.1101/2024.02.05.577574 · Cited by 2
Qiu, Y.-L., Wu, S.-F., Zhong, Y., Fan, D., Tong, Q., Xiong, J., Xu, K., Liu, G., Liu, E.-J., Li, X.-G., et al. (2026) · Molecular Psychiatry · doi:10.1038/s41380-026-03740-y · Cited by 1 · see citing works
Self-citationCha, Y., Leszczynska, A., Kagalwala, M. N., & Ross, J. (2026) · Journal of dementia and Alzheimer's disease · doi:10.3390/jdad3020017 · Cited by 1 · see citing works
“NMI is a co-regulator of STAT1 [46], whereas STAT1 has been reported to be elevated in AD and to function together to amplify interferon-driven inflammatory responses [47].”
Another pleiotropic effect of SGLT2 inhibitors: Is it a new frontier in thyroid function regulation?
Szklarz, M., Wołos-Kłosowicz, K., Szulc, J., Górny, J. M., Modzelewski, R., & Matuszewski, W. (2026) · Thyroid Research · doi:10.1186/s13044-025-00282-3 · Cited by 1 · see citing works
“Chronic upregulation of mTOR occurs in an anabolic state (elevated levels of glucose, amino acids, and growth factors) associated with excessive nutrition and lack of physical activity [105, 106].”
Sundaresh, S. N., Vogel, E. W., Hue, C. D., Zhang, H., Staniszewski, A., Berman, H. L., Gill, Z., Asam, K. R., Liang, S., Shen, L., et al. (2025) · Alzheimer s & Dementia · doi:10.1002/alz.70947 · Cited by 1 · see citing works
Editorial: The Molecular Mechanisms of Synaptic Plasticity Impairments in Alzheimer’s Disease
Liu, G., Lei, P., Dong, Z., & Li, S.-P. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.832728 · Cited by 3 · see citing works
“Overexpressing tau decreased NMDAR level by activation of STAT1 and inactivation of STAT3 (Li et al., 2019; Hong et al., 2020).”
BackgroundSelf-citationZhao, Y., Li, F., Li, S., Ji, J., Qiao, W., & Fang, J. (2022) · Human & Experimental Toxicology · doi:10.1177/09603271221129846 · Cited by 1 · see citing works
“Phosphorylation of STAT1 at Ser727 is required for the activation of STAT1.(29,30) Given that phosphorylation is pivotal for STAT1 activation, we noted that AlCl3 treatment increased STAT1 Ser727 phosphorylation compared to the control group, but had no significant effect on STAT1 phosphorylation at Tyr701 site.”
BackgroundInfluentialGuo, L., Liu, Y., & Wang, J. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.727928 · Cited by 1 · see citing works
Self-citationAcosta-Martínez, M., Carter, V., Nessim, A., Murphy, S. R., Dhawan, J., Beach, T., Serrano, G., Sundermann, E., & Biegon, A. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27198590
“In vitro and in vivo studies have shown complex interactions between tau and NMDARs, with studies suggesting that under pathological states, tau accumulation impairs synaptic plasticity through JAK2/STAT1-induced suppression of NMDAR expression [14].”
Epigenetic aging in Alzheimer's disease: Relation to proteome
Kim, B., Lee, H., Kim, J. P., Seo, S. W., Nho, K. T., & Initiative, A. D. N. (2026) · Alzheimer s & Dementia · doi:10.1002/alz.71732
The presynaptic protein bassoon is a biofluid biomarker of synaptic pathology in multiple sclerosis
Woo, M. S., Rothammer, N., Bal, L. C., Krisp, C., Kreutzfeldt, M., Witt, S., Maceski, A. M., Siebels, B., Raich, L., Mayer, C., et al. (2026) · EBioMedicine · doi:10.1016/j.ebiom.2026.106282
Zhou, Q., Sun, F., Zhang, Y., Cao, X., Li, M., Yu, H., Jiang, T., Li, S., Wang, W., Xie, J., et al. (2026) · MedComm · doi:10.1002/mco2.70665
Self-citationImplications of virus-induced stress granules in tauopathies
Sharma, S., Vandenakker, A., Cortes-Pérez, C. M., Milne, S., & Douville, R. N. (2026) · Translational Neurodegeneration · doi:10.1186/s40035-026-00538-4
Li, X., Li, T., Xiong, B., Luo, J., Yang, X., & Feng, Y. (2025) · Experimental Brain Research · doi:10.1007/s00221-025-07195-5
“The injection coordinates of hippocampal CA3 region as follows: ± 2.5 mm lateral, − 2.2 mm posterior, − 2.4 mm ven - tral (Li et al. 2019b, 2025 ).”
InfluentialSelf-citationGuo, H., Zhang, H., Zhang, C., Shen, Y., Jiang, L., Yang, M., Zhang, Y., Zhang, N., Zhang, R., Yu, R., et al. (2025) · JCI Insight · doi:10.1172/jci.insight.191347
“Further mechanistic research revealed that SH2D5 modulated the autophagic degradation of STAT1 to affect the transcription of NMDARs.”
InfluentialHuber, C. C., Callegari, E. A., Paez, M., Li, X., Dwamena, A., & Wang, H. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.02.09.579699 · Cited by 3 · see citing works
Self-citationKnockdown of MALAT1 attenuates pyroptosis in diabetic cerebral ischemia via STAT1
Zhao, N., Hua, W., Liu, Q., Wang, Y.-Y., Liu, Z.-Y., Jin, S.-N., Wang, B.-H., Pang, Y., Qi, J.-P., & Song, Y. (2021) · doi:10.21203/rs.3.rs-997349/v1
“STAT1-mediated downregulation of N-methyl-D-aspartate receptors contributes to hippocampal neuron degeneration and memory de cits [36].”
BackgroundSelf-citation4R Tau Modulates Cocaine-Associated Memory Through Adult Hippocampal NeurogenesisPreprint
Li, H., Xu, W., Wang, D., Fang, Q., Wang, L., Wan, X., Zhang, J., Hu, Y., Li, H., Zhang, J., et al. (2020) · doi:10.21203/rs.3.rs-74944/v1
“Tau accumulation plays an important role in memory impairment [32, 33], and a decrease in Tau expression prevents neuronal loss, amyloid beta-induced axonal transport de cits as well as memory impairment in tauopathy models [34–36].”
BackgroundSelf-citation
- Authors
- Li, X., Hong, X., Wang, Y., Zhang, S., Zhang, J., Li, X., Liu, Y., Sun, D., Feng, Q., Ye, J., Gao, Y., Ke, D., Wang, Q., Li, H., Ye, K., Liu, G., & Wang, J.
- Affiliations
- Wuhan Union Hospital (CN)
- Huazhong University of Science and Technology (CN)
- Emory University (US)
- Nantong University (CN)
- Corresponding author
- Liu, Gong‐Ping
- Wang, Jian‐Zhi
- Venue
- The EMBO Reports
- Published
- 2019-05-13
- Volume
- 20
- Issue
- 6
- ISSN
- 1469-221X (ISSN-L)
- 1469-3178
- PMC
- PMC6549025
- OpenAlex
- W2944387674
- Cited by
- 81
- References
- 0
- Citations by year
- 2026: 11 · 2025: 10 · 2024: 13 · 2023: 14 · 2022: 11 · 2021: 12 · 2020: 8 · 2019: 2
- FWCI
- 5.66
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- Locations
- EMBO Reports (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, other-oa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Ministry of Science and Technology of China (2016YFC13058001)
- Natural Science Foundation of China (31730035, 91632305, 81870846, 81721005)
- Sanming Project of Medicine in Shenzhen (SZSM201611090)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- tau accumulation, STAT1, NMDA receptor, memory impairment, synaptic plasticity, JAK2/STAT1 signaling, synaptic dysfunction, Alzheimer's disease
- MeSH terms
- Alzheimer Disease, Animals, Disease Models, Animal, Disease Susceptibility, Gene Expression Regulation, Humans, Memory Disorders, Models, Biological, Neuronal Plasticity, Phosphorylation, Promoter Regions, Genetic, Protein Binding, Signal Transduction, Receptors, N-Methyl-D-Aspartate, tau Proteins, Protein Transport, STAT1 Transcription Factor, Mice, Janus Kinase 2, Protein Interaction Domains and Motifs
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