Molecular Neurodegeneration最新文献

{"title":"Inhibition of soluble epoxide hydrolase confers neuroprotection and restores microglial homeostasis in a tauopathy mouse model","authors":"Shuo Wang, Chuangye Qi, Chetan Rajpurohit, Baijayanti Ghosh, Wen Xiong, Baiping Wang, Yanyan Qi, Sung Hee Hwang, Bruce D. Hammock, Hongjie Li, Li Gan, Hui Zheng","doi":"10.1186/s13024-025-00844-x","DOIUrl":"https://doi.org/10.1186/s13024-025-00844-x","url":null,"abstract":"The epoxyeicosatrienoic acids (EETs) are derivatives of the arachidonic acid metabolism with anti-inflammatory activities. However, their efficacy is limited due to the rapid hydrolysis by soluble epoxide hydrolase (sEH). Inhibition of sEH has been shown to stabilize the EETs and reduce neuroinflammation in Aβ mouse models of Alzheimer’s disease (AD). However, the role of the sEH-EET signaling pathway in other CNS cell types and neurodegenerative conditions are less understood. Here we investigated the mechanisms and functional role of the sEH-EET axis in tauopathy by treating PS19 mice with a small molecule sEH inhibitor TPPU and by crossing the PS19 mice with Ephx2 (gene encoding sEH) knockout mice. This was followed by single-nucleus RNA-sequencing (snRNA-seq), biochemical and immunohistochemical analysis, and behavioral assessments. Additionally, we examined the effects of the sEH-EET pathway in primary microglia cultures and human induced pluripotent stem cell (iPSC)-derived neurons exhibiting seeding-induced Tau inclusions. sEH inhibition improved cognitive function, rescued neuronal cell loss, and reduced Tau pathology and microglial reactivity. snRNA-seq revealed that TPPU treatment upregulated genes involved in actin cytoskeleton and excitatory synaptic pathways. Treatment of human iPSC-derived neurons with TPPU enhanced synaptic density without affecting Tau accumulation, suggesting a cell-autonomous neuroprotective effect of sEH blockade. Furthermore, sEH inhibition reversed disease-associated and interferon-responsive microglial states in PS19 mice, while EET supplementation promoted Tau phagocytosis and clearance in primary microglia cultures. These findings demonstrate that sEH blockade or EET augmentation confers therapeutic benefit in neurodegenerative tauopathies by simultaneously targeting neuronal and microglial pathways.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"19 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143862742","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Increased TMEM106B levels lead to lysosomal dysfunction which affects synaptic signaling and neuronal health","authors":"Jolien Perneel, Miranda Lastra Osua, Sara Alidadiani, Nele Peeters, Linus De Witte, Bavo Heeman, Simona Manzella, Riet De Rycke, Mieu Brooks, Ralph B. Perkerson, Elke Calus, Wouter De Coster, Manuela Neumann, Ian R. A. Mackenzie, Debby Van Dam, Bob Asselbergh, Tommas Ellender, Xiaolai Zhou, Rosa Rademakers","doi":"10.1186/s13024-025-00831-2","DOIUrl":"https://doi.org/10.1186/s13024-025-00831-2","url":null,"abstract":"Genetic variation in Transmembrane protein 106B (TMEM106B) is known to influence the risk and presentation in several neurodegenerative diseases and modifies healthy aging. While evidence from human studies suggests that the risk allele is associated with higher levels of TMEM106B, the contribution of elevated levels of TMEM106B to neurodegeneration and aging has not been assessed and it remains unclear how TMEM106B modulates disease risk. To study the effect of increased TMEM106B levels, we generated Cre-inducible transgenic mice expressing human wild-type TMEM106B. We evaluated lysosomal and neuronal health using in vitro and in vivo assays including transmission electron microscopy, immunostainings, behavioral testing, electrophysiology, and bulk RNA sequencing. We created the first transgenic mouse model that successfully overexpresses TMEM106B, with a 4- to 8-fold increase in TMEM106B protein levels in heterozygous (hTMEM106B(+)) and homozygous (hTMEM106B(++)) animals, respectively. We showed that the increase in TMEM106B protein levels induced lysosomal dysfunction and age-related downregulation of genes associated with neuronal plasticity, learning, and memory. Increased TMEM106B levels led to altered synaptic signaling in 12-month-old animals which further exhibited an anxiety-like phenotype. Finally, we observed mild neuronal loss in the hippocampus of 21-month-old animals. Characterization of the first transgenic mouse model that overexpresses TMEM106B suggests that higher levels of TMEM106B negatively impacts brain health by modifying brain aging and impairing the resilience of the brain to the pathomechanisms of neurodegenerative disorders. This novel model will be a valuable tool to study the involvement and contribution of increased TMEM106B levels to aging and will be essential to study the many age-related diseases in which TMEM106B was genetically shown to be a disease- and risk-modifier. ","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"13 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143862740","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Therapeutic effects of adipose-derived mesenchymal stem cells combined with glymphatic system activation in prion disease","authors":"Mohammed Zayed, Yong-Chan Kim, Byung-Hoon Jeong","doi":"10.1186/s13024-025-00835-y","DOIUrl":"https://doi.org/10.1186/s13024-025-00835-y","url":null,"abstract":"There is currently no effective therapy for prion diseases. The glymphatic system is an organized system of perivascular spaces that facilitates the removal of metabolic waste from the brain. This study demonstrates the therapeutic potential of a combination therapy of adipose-derived mesenchymal stem cells (AdMSCs) and a glymphatic system-activated drug, clonidine, against prion disease. The therapy has the potential to clear PrPSc accumulation, ameliorate astrocytosis, and prolong the survival time of ME7-infected mice.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"42 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143841291","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TREM2 and sTREM2 in Alzheimer’s disease: from mechanisms to therapies","authors":"Lianshuai Zhang, Xianyuan Xiang, Yahui Li, Guojun Bu, Xiao-Fen Chen","doi":"10.1186/s13024-025-00834-z","DOIUrl":"https://doi.org/10.1186/s13024-025-00834-z","url":null,"abstract":"Triggering receptor expressed on myeloid cells 2 (TREM2) is an innate immune receptor predominantly expressed by microglia in the brain. Recent studies have established TREM2 as a central immune signaling hub in neurodegeneration, where it triggers immune responses upon sensing pathological development and tissue damages. TREM2 binds diverse ligands and activates downstream pathways that regulate microglial phagocytosis, inflammatory responses, and metabolic reprogramming. Interestingly, TREM2 exists both in its membrane-bound form and as a soluble variant (sTREM2), that latter is generated through proteolytic shedding or alternative splicing and can be detected in cerebrospinal fluid and plasma. Emerging clinical and preclinical evidence underscores the potential of TREM2 and sTREM2 as diagnostic biomarkers and therapeutic targets in Alzheimer’s disease (AD). This review provides a comprehensive overview of the molecular functions, regulatory mechanisms, and pathological implications of TREM2 and sTREM2 in AD. Furthermore, we explore their potential roles in diagnostics and therapeutics while suggesting key research directions for advancing TREM2/sTREM2-based strategies in combating AD.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"39 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143841290","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ASO-mediated knock-down of GPNMB in mutant-GRN and in Grn-deficient peripheral myeloid cells disrupts lysosomal function and immune responses","authors":"Rebecca L. Wallings, Drew A. Gillett, Hannah A. Staley, Savanna Mahn, Julian Mark, Noelle Neighbarger, Holly Kordasiewicz, Warren D. Hirst, Malú Gámez Tansey","doi":"10.1186/s13024-025-00829-w","DOIUrl":"https://doi.org/10.1186/s13024-025-00829-w","url":null,"abstract":"GPNMB has been discussed as a potential therapeutic target in GRN-mediated neurodegeneration, based on the observed reproducible upregulation in FTD-GRN cerebrospinal fluid (CSF) and post-mortem brain. However, the functional impacts of up-regulated GPNMB are currently unknown, and it is currently unclear if targeting GPNMB will be protective or deleterious. Increases in GPNMB seen in FTD-GRN are reproduced in brains of aged Grn-deficient mice. Importantly, although brains of young Grn-deficient mice do not exhibit upregulated Gpnmb expression, peripheral immune cells of these mice exhibit increased Gpnmb expression as young as 5-to-6 months, suggesting the effects of Grn-deficiency in the periphery proceed those in the brain. Grn-deficiency is known to alter peripheral immune cell function, including impaired autophagy and altered cytokine secretion. GPNMB has potential effects on these processes, but has never been studied in peripheral immune cells of patients or preclinical models. Informing the functional significance of GPNMB upregulation in Grn-deficient states in myeloid cells has potential to inform GPNMB as a therapeutic candidate. The effects of GPNMB knock-down via antisense oligonucleotide (ASO) were assessed in peripheral blood mononuclear cells (PBMCs) from 25 neurologically healthy controls (NHCs) and age- and sex-matched FTD-GRN patients, as well as peritoneal macrophages (pMacs) from progranulin-deficient (Grn -/-) and B6 mice. Lysosomal function, antigen presentation and MHC-II processing and recycling were assessed, as well as cytokine release and transcription. ASO-mediated knock-down of GPNMB increased lysosomal burden and IL1β cytokine secretion in FTD-GRN carriers and NHCs monocytes. ASO-mediated knock-down of Gpnmb in Grn-deficient macrophages decreased lysosomal pan-cathepsin activity and protein degradation. In addition, ASO-mediated knock-down of Gpnmb increased MHC-II surface expression, which was driven by decreased MHC-II uptake and recycling, in macrophages from Grn-deficient females. Finally, ASO-mediated knock-down of Gpnmb dysregulated IFN $$gamma$$ -stimulated IL6 cytokine transcription and secretion by mouse macrophages due to the absence of regulatory actions of the Gpnmb extracellular fragment (ECF). Our data herein reveal that GPNMB has a regulatory effect on multiple immune effector functions, including capping inflammation and immune responses in myeloid cells, potentially via secretion of its ECF. Therefore, in progranulin-deficient states, the marked upregulation in GPNMB transcript and protein may represent a compensatory mechanism to preserve lysosomal function in myeloid cells. These novel findings indicate that targeted depletion of GPNMB in FTD-GRN would not be a rational therapeutic strategy because it is likely to dysregulate important immune cell effector functions mediated by GPNMB. Specifically, our data indicate that therapeutic strategies inhibiting GPNMB levels and/or activity may worsen th","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"95 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143805720","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Immune modulation to treat Alzheimer’s disease","authors":"Michael R. Duggan, David G. Morgan, Brittani R. Price, Binita Rajbanshi, Alfonso Martin-Peña, Malú Gámez Tansey, Keenan A. Walker","doi":"10.1186/s13024-025-00828-x","DOIUrl":"https://doi.org/10.1186/s13024-025-00828-x","url":null,"abstract":"Immune mechanisms play a fundamental role in Alzheimer’s disease (AD) pathogenesis, suggesting that approaches which target immune cells and immunologically relevant molecules can offer therapeutic opportunities beyond the recently approved amyloid beta monoclonal therapies. In this review, we provide an overview of immunomodulatory therapeutics in development, including their preclinical evidence and clinical trial results. Along with detailing immune processes involved in AD pathogenesis and highlighting how these mechanisms can be therapeutically targeted to modify disease progression, we summarize knowledge gained from previous trials of immune-based interventions, and provide a series of recommendations for the development of future immunomodulatory therapeutics to treat AD.\u0000","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"38 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143736689","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A stress-dependent TDP-43 SUMOylation program preserves neuronal function","authors":"Terry R. Suk, Caroline E. Part, Jenny L. Zhang, Trina T. Nguyen, Meghan M. Heer, Alejandro Caballero-Gómez, Veronica S. Grybas, Paul M. McKeever, Benjamin Nguyen, Tahir Ali, Steve M. Callaghan, John M. Woulfe, Janice Robertson, Maxime W. C. Rousseaux","doi":"10.1186/s13024-025-00826-z","DOIUrl":"https://doi.org/10.1186/s13024-025-00826-z","url":null,"abstract":"Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) are overwhelmingly linked to TDP-43 dysfunction. Mutations in TDP-43 are rare, indicating that the progressive accumulation of exogenous factors – such as cellular stressors – converge on TDP-43 to play a key role in disease pathogenesis. Post translational modifications such as SUMOylation play essential roles in response to such exogenous stressors. We therefore set out to understand how SUMOylation may regulate TDP-43 in health and disease. We find that TDP-43 is regulated dynamically via SUMOylation in response to cellular stressors. When this process is blocked in vivo, we note age-dependent TDP-43 pathology and sex-specific behavioral deficits linking TDP-43 SUMOylation with aging and disease. We further find that SUMOylation is correlated with human aging and disease states. Collectively, this work presents TDP-43 SUMOylation as an early physiological response to cellular stress, disruption of which may confer a risk for TDP-43 proteinopathy.\u0000","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"41 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143723167","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Decoding microglial immunometabolism: a new frontier in Alzheimer's disease research","authors":"Eun Sun Jung, Hayoung Choi, Inhee Mook-Jung","doi":"10.1186/s13024-025-00825-0","DOIUrl":"https://doi.org/10.1186/s13024-025-00825-0","url":null,"abstract":"Alzheimer’s disease (AD) involves a dynamic interaction between neuroinflammation and metabolic dysregulation, where microglia play a central role. These immune cells undergo metabolic reprogramming in response to AD-related pathology, with key genes such as TREM2, APOE, and HIF-1α orchestrating these processes. Microglial metabolism adapts to environmental stimuli, shifting between oxidative phosphorylation and glycolysis. Hexokinase-2 facilitates glycolytic flux, while AMPK acts as an energy sensor, coordinating lipid and glucose metabolism. TREM2 and APOE regulate microglial lipid homeostasis, influencing Aβ clearance and immune responses. LPL and ABCA7, both associated with AD risk, modulate lipid processing and cholesterol transport, linking lipid metabolism to neurodegeneration. PPARG further supports lipid metabolism by regulating microglial inflammatory responses. Amino acid metabolism also contributes to microglial function. Indoleamine 2,3-dioxygenase controls the kynurenine pathway, producing neurotoxic metabolites linked to AD pathology. Additionally, glucose-6-phosphate dehydrogenase regulates the pentose phosphate pathway, maintaining redox balance and immune activation. Dysregulated glucose and lipid metabolism, influenced by genetic variants such as APOE4, impair microglial responses and exacerbate AD progression. Recent findings highlight the interplay between metabolic regulators like REV-ERBα, which modulates lipid metabolism and inflammation, and Syk, which influences immune responses and Aβ clearance. These insights offer promising therapeutic targets, including strategies aimed at HIF-1α modulation, which could restore microglial function depending on disease stage. By integrating metabolic, immune, and genetic factors, this review underscores the importance of microglial immunometabolism in AD. Targeting key metabolic pathways could provide novel therapeutic strategies for mitigating neuroinflammation and restoring microglial function, ultimately paving the way for innovative treatments in neurodegenerative diseases.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"57 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143712966","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Immune cell metabolic dysfunction in Parkinson’s disease","authors":"Julian R. Mark, Malú Gámez Tansey","doi":"10.1186/s13024-025-00827-y","DOIUrl":"https://doi.org/10.1186/s13024-025-00827-y","url":null,"abstract":"Parkinson’s disease (PD) is a multi-system disorder characterized histopathologically by degeneration of dopaminergic neurons in the substantia nigra pars compacta. While the etiology of PD remains multifactorial and complex, growing evidence suggests that cellular metabolic dysfunction is a critical driver of neuronal death. Defects in cellular metabolism related to energy production, oxidative stress, metabolic organelle health, and protein homeostasis have been reported in both neurons and immune cells in PD. We propose that these factors act synergistically in immune cells to drive aberrant inflammation in both the CNS and the periphery in PD, contributing to a hostile inflammatory environment which renders certain subsets of neurons vulnerable to degeneration. This review highlights the overlap between established neuronal metabolic deficits in PD with emerging findings in central and peripheral immune cells. By discussing the rapidly expanding literature on immunometabolic dysfunction in PD, we aim to draw attention to potential biomarkers and facilitate future development of immunomodulatory strategies to prevent or delay the progression of PD.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"47 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143677912","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role of n-3-derived specialised pro-resolving mediators (SPMs) in microglial mitochondrial respiration and inflammation resolution in Alzheimer’s disease","authors":"Mary Slayo, Christoph Rummel, Pasindu Hansana Singhaarachchi, Martin Feldotto, Sarah J. Spencer","doi":"10.1186/s13024-025-00824-1","DOIUrl":"https://doi.org/10.1186/s13024-025-00824-1","url":null,"abstract":"Alzheimer’s disease (AD) is the most common form of dementia globally and is characterised by reduced mitochondrial respiration and cortical deposition of amyloid-β plaques and neurofibrillary tangles comprised of hyper-phosphorylated tau. Despite its characterisation more than 110 years ago, the mechanisms by which AD develops are still unclear. Dysregulation of microglial phagocytosis of amyloid-β may play a key role. Microglia are the major innate immune cell of the central nervous system and are critical responders to pro-inflammatory states. Typically, microglia react with a short-lived inflammatory response. However, a dysregulation in the resolution of this microglial response results in the chronic release of inflammatory mediators. This prolongs the state of neuroinflammation, likely contributing to the pathogenesis of AD. In addition, the microglial specialised pro-resolving mediator (SPM) contribution to phagocytosis of amyloid-β is dysregulated in AD. SPMs are derivatives of dietary n-3 polyunsaturated fatty acids (PUFAs) and potentially represent a strategic target for protection against AD progression. However, there is little understanding of how mitochondrial respiration in microglia may be sustained long term by n-3-derived SPMs, and how this affects their clearance of amyloid-β. Here, we re-evaluate the current literature on SPMs in AD and propose that SPMs may improve phagocytosis of amyloid-β by microglia as a result of sustained mitochondrial respiration and allowing a pro-resolution response.\u0000","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"70 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143666067","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}