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多肽靶向嵌合体通过促进tau蛋白特异性去磷酸化治疗阿尔茨海默病和其他tau蛋白病

Science Bulletin 2024年第8期69卷 1137-1152页

作者：苏静芬肖越魏林郁雷慧杨孙飞王围霞尹君熊瑞李师宏张配周颖王小川郑杰王建枝 Department of Pathophysiology School of Basic MedicineKey Laboratory of Education Ministry of China/Hubei Province for Neurological DisordersTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430030China School of Artificial Intelligence and Automation Huazhong University of Science and TechnologyWuhan 430030China Sino-UK Joint Laboratory of Brain Function and Injury of Henan Province Department of Physiology and PathophysiologySchool of Basic Medical SciencesXinxiang Medical UniversityXinxiang 453003China Department of Pathophysiology School of Basic Medical SciencesWuhan UniversityWuhan 430030China Department of Anesthesiology The First Affiliated Hospital of Gannan Medical UniversityGanzhou 341000China The Core Facility and Technical Support Wuhan Institute of VirologyChinese Academy of SciencesWuhan 430030China Research Center for Medicine and Structural Biology Wuhan UniversityWuhan 430030China Neuroscience Research Institute and Department of Neurobiology School of Basic Medical SciencesPeking UniversityKey Laboratory for NeuroscienceMinistry of Education/National Health CommissionBeijing 100083China Co-innovation Center of Neuroregeneration Nantong UniversityNantong 226000China

Abnormal hyperphosphorylation and accumulation of tau protein play a pivotal role in neurodegeneration in Alzheimer’s disease(AD)and many other tauopathies.Selective elimination of hyperphosphorylated tau is promising for the therapy of these diseases.We have conceptualized a strategy,named dephosphorylation-targeting chimeras(DEPTACs),for specifically hijacking phosphatases to tau to debilitate its hyperphosphorylation.Here,we conducted the step-by-step optimization of each constituent motif to generate DEPTACs with reasonable effectiveness in facilitating the dephosphorylation and subsequent clearance of pathological tau.Specifically,for one of the selected chimeras,D16,we demonstrated its significant efficiency in rescuing the neurodegeneration caused by neurotoxic K18-tau seeds in vitro.Moreover,intravenous administration of D16 also alleviated tau pathologies in the brain and improved memory deficits in AD mice.These results suggested DEPTACs as targeted modulators of tau phosphorylation,which hold therapeutic potential for AD and other tauopathies.

关键词： tau Dephosphorylation-targeting chimeras Therapeutic potential tauopathy

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Neural stem cell transplantation alleviates functional cognitive deficits in a mouse model of tauopathy

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Neural Regeneration Research 2022年第1期17卷 152-162页

作者： He-Ao Zhang Chun-Xu Yuan Ke-Fu Liu Qi-Fan Yang Juan Zhao Hui Li Qing-Hu Yang Da Song Zhen-Zhen Quan Hong Qing Key Laboratory of Molecular Medicine and Biotherapy School of Life ScienceBeijing Institute of TechnologyBeijingChina

The mechanisms of the transplantation of neural stem cells(NSCs)in the treatment of Alzheimer’s disease remain poorly understood.In this study,NSCs were transplanted into the hippocampal CA1 region of the rTg(tau P301L)4510 mouse model,a tauopathy model that is thought to reflect the tau pathology associated with Alzheimer’s disease.The results revealed that NSC transplantation reduced the abnormal aggregation of tau,resulting in significant improvements in the short-term memory of the tauopathy model mice.Compared with wild-type and phosphate-buffered saline(PBS)-treated mice,mice that received NSC transplantations were characterized by changes in the expression of multiple proteins in brain tissue,particularly those related to the regulation of tau aggregation or misfolding.Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway analysis and Gene Ontology(GO)function analysis revealed that these proteins were primarily enriched in pathways associated with long-term potentiation,neurogenesis,and other neurobiological processes.Changes in the expression levels of key proteins were verified by western blot assays.These data provided clues to improve the understanding of the functional capacity associated with NSC transplantation in Alzheimer’s disease treatment.This study was approved by the Beijing Animal Ethics Association and Ethics Committee of Beijing Institute of Technology(approval No.SYXK-BIT-school of life science-2017-M03)in 2017.

关键词： Alzheimer’s disease cell transplantation neural differentiation neural stem cells proteomic analysis short-term memory tauopathy

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Surfen and oxalyl surfen decrease tau hyperphosphorylation and mitigate neuron deficits in vivo in a zebrafish model of tauopathy

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Translational Neurodegeneration 2018年第1期7卷 54-62页

作者： Seyedeh Maryam Alavi Naini Constantin Yanicostas Rahma Hassan-Abdi Sébastien Blondeel Mohamed Bennis Ryan J.Weiss Yitzhak Tor Jeffrey D.Esko Nadia Soussi-Yanicostas PROTECT InsermUniversitéParis DiderotSorbonne Paris CitéParisFrance Institut de Biologie Paris Seine-Laboratoire Neuroscience Paris Seine Inserm UMRS 1130CNRS UMR 8246UPMC UM 118UniversitéPierre et Marie CurieParisFrance Cadi Ayyad University MarrakeshMorocco Department of Chemistry and Biochemistry University of CaliforniaSan DiegoLa JollaCAUSA Department of Cellular and Molecular Medicine University of CaliforniaSan DiegoLa JollaCAUSA

Background:Tauopathies comprise a family of neurodegenerative disorders including Alzheimer’s disease for which there is an urgent and unmet need for disease-modifying treatments.Tauopathies are characterized by pathological tau hyperphosphorylation,which has been shown to correlate tightly with disease progression and memory loss in patients suffering from Alzheimer’s disease.We recently demonstrated an essential requirement for 3-O-sulfated heparan sulfate in pathological tau hyperphosphorylation in zebrafish,a prominent model organism for human drug discovery.Here,we investigated whether in vivo treatment with surfen or its derivatives oxalyl surfen and hemisurfen,small molecules with heparan sulfate antagonist properties,could mitigate tau hyperphosphorylation and neuronal deficits in a zebrafish model of tauopathies.Results:In vivo treatment of Tg[HuC::hTau^(P301L);DsRed]embryos for 2 days with surfen or oxalyl surfen significantly reduced the accumulation of the pThr181 tau phospho-epitope measured by ELISA by 30%and 51%,respectively.Western blot analysis also showed a significant decrease of pThr181 and pSer396/pSer404 in embryos treated with surfen or oxalyl surfen.Immunohistochemical analysis further confirmed that treatment with surfen or oxalyl surfen significantly decreased the AT8 tau epitope in spinal motoneurons.In addition,in vivo treatment of Tg[HuC::hTau^(P301L);DsRed]embryos with surfen or oxalyl surfen significantly rescued spinal motoneuron axon-branching defects and,as a likely consequence,the impaired stereotypical touch-evoked escape response.Importantly,treatment with hemisurfen,a surfen derivative devoid of heparan sulfate antagonist activity,does not affect tau hyperphosphorylation,nor neuronal or behavioural deficits in Tg[HuC::hTau^(P301L);DsRed]embryos.Conclusion:Our findings demonstrate for the first time that surfen,a well-tolerated molecule in clinical settings,and its derivative,oxalyl surfen,could mitigate or delay neuronal defects in tauopathies,including Alzheimer’s disease.

关键词： tauopathy Zebrafish Alzheimer’s disease Tau protein Tau hyperphosphorylation Surfen Oxalyl surfen Heparan sulfate

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Towards understandings of serine/arginine-rich splicing factors

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Acta Pharmaceutica Sinica B 2023年第8期13卷 3181-3207页

作者： Dianyang Li Wenying Yu Maode Lai School of Basic Medicine and Clinical Pharmacy China Pharmaceutical UniversityNanjing 210009China State Key Laboratory of Natural Medicines China Pharmaceutical UniversityNanjing 210009China Department of Pathology Research Unit of Intelligence Classification of Tumor Pathology and Precision TherapyChinese Academy of Medical Science(2019RU042)Key Laboratory of Disease Proteomics of Zhejiang ProvinceZhejiang University School of MedicineHangzhou 310058China

Serine/arginine-rich splicing factors(SRSFs)refer to twelve RNA-binding proteins which regulate splice site recognition and spliceosome assembly during precursor messenger RNA splicing.SRSFs also participate in other RNA metabolic events,such as transcription,translation and nonsensemediated decay,during their shuttling between nucleus and cytoplasm,making them indispensable for genome diversity and cellular activity.Of note,aberrant SRSF expression and/or mutations elicit fallacies in gene splicing,leading to the generation of pathogenic gene and protein isoforms,which highlights the therapeutic potential of targeting SRSF to treat diseases.In this review,we updated current understanding of SRSF structures and functions in RNA metabolism.Next,we analyzed SRSF-induced aberrant gene expression and their pathogenic outcomes in cancers and non-tumor diseases.The development of some well-characterized SRSF inhibitors was discussed in detail.We hope this review will contribute to future studies of SRSF functions and drug development targeting SRSFs.

关键词： Alternative splicing RNA metabolism Cancer therapy tauopathy Autoimmunediseases Small molecule inhibitor

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Crry silencing alleviates Alzheimer’s disease injury by regulating neuroinflammatory cytokines and the complement system

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Neural Regeneration Research 2022年第8期17卷 1841-1849页

作者： Xi-Chen Zhu Lu Liu Wen-Zhuo Dai Tao Ma Department of Neurology Wuxi No.2 People’s Hospital of Nanjing Medical UniversityWuxiJiangsu ProvinceChina Department of Neurology Wuxi No.2 People’s HospitalAffiliated Wuxi Clinical College of Nantong UniversityWuxiJiangsu ProvinceChina

Complement component(3b/4b)receptor 1(CR1)expression is positively related to the abundance of phosphorylated microtubule-associated protein tau(tau),and CR1 expression is associated with susceptibility to Alzheimer’s disease.However,the exact role of CR1 in tau protein-associated neurodegenerative diseases is unknown.In this study,we show that the mouse Cr1-related protein Y(Crry)gene,Crry,is localized to microglia.We also found that Crry protein expression in the hippocampus and cortex was significantly elevated in P301S mice(a mouse model widely used for investigating tau pathology)compared with that in wild-type mice.Tau protein phosphorylation(at serine 202,threonine 205,threonine 231,and serine 262)and expression of the major tau kinases glycogen synthase kinase-3 beta and cyclin-dependent-like kinase 5 were greater in P301S mice than in wild-type mice.Crry silencing by lentivirus-transfected short hairpin RNA led to greatly reduced tau phosphorylation and glycogen synthase kinase-3 beta and cyclin-dependent-like kinase 5 activity.Crry silencing reduced neuronal apoptosis and rescued cognitive impairment of P301S mice.Crry silencing also reduced the levels of the neuroinflammatory factors interleukin-1 beta,tumor necrosis factor alpha,and interleukin-6 and the complement components complement 3 and complement component 3b.Our results suggest that Crry silencing in the P301S mouse model reduces tau protein phosphorylation by reducing the levels of neuroinflammation and complement components,thereby improving cognitive function.

关键词： Alzheimer’s disease cognitive function complement system CR1 Crry neurodegeneration neuroinflammation tauopathy

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Anti-IgLON5 disease: a novel topic beyond neuroimmunology

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Neural Regeneration Research 2023年第5期18卷 1017-1022页

作者： Yi-ZongHeng Zhang You Ni Yi-Ning Gao Ding-Ding Shen Lu He Dou Yin Huan-Yu Meng Qin-Ming Zhou Ji Hu Sheng Chen Department of Neurology&Institute of Neurology Ruijin HospitalAffiliated with Shanghai Jiao Tong University School of MedicineShanghaiChina Co-Innovation Center of Neuroregeneration Nantong UniversityNantongJiangsu ProvinceChina School of Life Science and Technology ShanghaiTech UniversityShanghaiChina Shanghai Key Laboratory of Psychotic Disorders Shanghai Mental Health CenterShanghaiChina

Anti-IgLON5 disease is a recently defined autoimmune disorder of the nervous system associated with autoantibodies against IgLON5. Given its broad clinical spectrum and extremely complex pathogenesis, as well as difficulties in its early diagnosis and treatment, anti-IgLON5 disease has become the subject of considerable research attention in the field of neuroimmunology. Anti-IgLON5 disease has characteristics of both autoimmunity and neurodegeneration due to the unique activity of the antiIgLON5 antibody. Neuropathologic examination revealed the presence of a tauopathy preferentially affecting the hypothalamus and brainstem tegmentum, potentially broadening our understanding of tauopathies. In contrast to that seen with other autoimmune encephalitis-related antibodies, basic studies have demonstrated that IgLON5 antibody-induced neuronal damage and degeneration are irreversible, indicative of a potential link between autoimmunity and neurodegeneration in antiIgLON5 disease. Herein, we comprehensively review and discuss basic and clinical studies relating to anti-IgLON5 disease to better understand this complicated disorder.

关键词： anti-IgLON5 disease autoimmune encephalitis human leukocyte antigen IgG4-related diseases IgLON5 antibody IgLONs immunotherapy inflammation neurodegeneration neuroimmunology tauopathy

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Propagation of tau and α-synuclein in the brain: therapeutic potential of the glymphatic system

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Translational Neurodegeneration 2022年第1期11卷 667-689页

作者： Douglas M.Lopes Sophie K.Llewellyn Ian F.Harrison Division of Medicine Department of ImagingCentre for Advanced Biomedical ImagingFaculty of Medical SciencesUniversity College LondonPaul O’Gorman Building72 Huntley StreetLondon WC1E 6DDUK

Many neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease, are characterised by the accumulation of misfolded protein deposits in the brain, leading to a progressive destabilisation of the neuronal network and neuronal death. Among the proteins that can abnormally accumulate are tau and α-synuclein, which can propagate in a prion-like manner and which upon aggregation, represent the most common intracellular proteinaceous lesions associated with neurodegeneration. For years it was thought that these intracellular proteins and their accumulation had no immediate relationship with extracellular homeostasis pathways such as the glymphatic clearance system;however, mounting evidence has now suggested that this is not the case. The involvement of the glymphatic system in neurodegenerative disease is yet to be fully defined;however, it is becoming increasingly clear that this pathway contributes to parenchymal solute clearance. Importantly, recent data show that proteins prone to intracellular accumulation are subject to glymphatic clearance, suggesting that this system plays a key role in many neurological disorders. In this review, we provide a background on the biology of tau and α-synuclein and discuss the latest findings on the cell-to-cell propagation mechanisms of these proteins. Importantly, we discuss recent data demonstrating that manipulation of the glymphatic system may have the potential to alleviate and reduce pathogenic accumulation of propagation-prone intracellular cytotoxic proteins. Furthermore, we will allude to the latest potential therapeutic opportunities targeting the glymphatic system that might have an impact as disease modifiers in neurodegenerative diseases.

关键词： Glymphatic Propagation tauopathy Synucleinopathy Clearance Aquaporin-4

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Cornel Iridoid Glycoside Suppresses Hyperactivity Phenotype in rTg4510 Mice through Reducing Tau Pathology and Improving Synaptic Dysfunction

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Current Medical Science 2020年第6期40卷 1031-1039页

作者： Deng-lei MA Yi LUO Rui HUANG Zi-run ZHAO Li ZhANG Ya-li LI Qi WANG Lin LI Lan ZhANG Department of Pharmacy Xuanwu Hospital of Capital Medical UniversityKey Laboratory for Neurodegenerative Diseases of Ministry of EducationBeijing Institute for Brain DisordersBeijing Engineering Research Center for Nerve System DrugsBeijing 100053China Institute of Clinical Pharmacology Guangzhou University of Chinese MedicineGuangzhou 510006China Renaissance School of Medicine at Stony Brook University Stony BrookNew York 11794USA

rTg4510 mice are transgenic mice expressing P301L mutant tau and have been developed as an animal model of tauopathies including Alzheimer’s disease(AD).Besides cognitive impairments,rTg4510 mice also show abnormal hyperactivity behavior.Cornel iridoid glycoside(CIG)is an active ingredient extracted from Cornus officinalis,a traditional Chinese herb.The purpose of the present study was to investigate the effects of CIG on the emotional disorders such as hyperactivity,and related mechanisms.The emotional hyperactivity was detected by locomotor activity test and Y maze test.Immunofluorescent and immunohistochemical analyses were conducted to measure neuron loss and phosphorylated tau.Western blotting was used to detect the expression of related proteins.The results showed that intragastric administration of CIG for 3 months decreased the hyperactivity phenotype,prevented neuronal loss,reduced tau hyperphosphorylation and aggregation in the amygdala of rTg4510 mice.Meanwhile,CIG alleviated the synaptic dysfunction by increasing the expression of N-methyl-D-aspartate receptors(NMDARs)subunits GluN1 and GluN2A andαamino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor(AMPAR)subunits GluA1 and GluA2,and increased the level of phosphorylated Ca2+/calmodulin dependent protein kinase IIα(p-CaMK IIα)in the brain of rTg4510 mice.In conclusion,CIG may have potential to treat the emotional disorders in tauopathies such as AD through reducing tau pathology and improving synaptic dysfunction.

关键词： cornel iridoid glycoside rTg4510 mouse hyperactivity tauopathy Alzheimer’s disease tau phosphorylation synaptic function

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Aberrant Activation of Cdc2/cyclin B1 Is Involved in Initiation of Cytoskeletal Pathology in Murine Niemann-Pick Disease Type C

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Journal of Huazhong University of Science and Technology(Medical Sciences) 2017年第5期37卷 732-739页

作者：巴黎李志军卜碧涛王伟张旻 Department of Neurology Tongji Hospital Tongji Medical College Huazhong University of Science and Technology

Niemann-Pick disease type C（NPC） is a fatal, neurovisceral lipid storage disease, neuropathologically characterized by cytoplasmic sequestration of glycolipids in neurons, progressive neuronal loss, neurofibrillary tangles（NFTs） formation, and axonal spheroids（AS）. Cytoskeletal pathology including accumulation of hyperphosphorylated cytoskeletal proteins is a neuropathological hallmark of the mouse model of NPC（npc mice）. With a goal of elucidating the mechanisms underlying the lesion formation, we investigated the temporal and spatial characteristics of cytoskeletal lesions and the roles of cdc2, cdk4, and cdk5 in lesion formation in young npc mice. Cytoskeletal lesions were detectable in npc mice at three weeks of age. Importantly, concomitant activation of cdc2/cyclin B1 kinase and accumulation of a subsequently generated cohort of phospho-epitopes were detected. The activation of cdk4/cyclin D1 and cdk5/p25 kinases was observed during the fourth week of life in npc mice, and this activation contributed to the lesion formation. We concluded that the progression of cytoskeletal pathology in npc mice older than four weeks is accelerated by the cumulative effect of cdc2, cdk4, and cdk5 activation. Furthermore, cdc2/cyclin B1 may act as a key initial player one week earlier. Targeting cell cycle activation may be beneficial to slow down the NPC pathogenesis.

关键词： cdc2 cdk4 cdk5 neurodegeneration Niemann-Pick disease type C axonal spheroid tauopathy

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Advances in the Pathogenesis of Alzheimer’s Disease:Focusing on Tau-Mediated Neurodegeneration

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Translational Neurodegeneration 2012年第1期1卷 192-198页

作者： Yale Duan Suzhen Dong Feng Gu Yinghe Hu Zheng Zhao Key Laboratory of Brain Functional Genomics Ministry of EducationShanghai Key Laboratory of Brain Functional GenomicsEast China Normal University3663 Zhongshan Road(N)Shanghai 200062China Shanghai Engineering Research Center for Molecular Therapeutics and New Drug Development East China Normal UniversityShanghai 200062China

In addition to senile plaques and cerebral amyloid angiopathy,the hyperphosphorylation of tau protein and formation of intraneuronal neurofibrillary tangles(NFTs)represents another neuropathological hallmark in AD brain.Tau is a microtubule-associated protein and localizes predominantly in the axons of neurons with the primary function in maintaining microtubules stability.When the balance between tau phosphorylation and dephosphorylation is changed in favor of the former,tau is hyperphosphorylated and the level of the free tau fractions elevated.The hyperphosphorylation of tau protein and formation of NFTs represent a characteristic neuropathological feature in AD brain.We have discussed the role of Aβin AD in our previous review,this review focused on the recent advances in tau-mediated AD pathology,mainly including tau hyperphosphorylation,propagation of tau pathology and the relationship between tau and Aβ.

关键词： Alzheimer’s disease Tau A-beta tauopathy Tau hyperphosphorylation Intraneuronal neurofibrillary tangles

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