Pub Date : 2025-08-29DOI: 10.1186/s13024-025-00886-1
Denise Balta, Anish Varghese, Susy Prieto Huarcaya, Alessandro Di Spiezio, André R. A. Marques, Enes Yağız Akdaş, Doğa Tabakacilar, Alice Drobny, Christian Werner, Wei Xiang, Rebecca Mächtel, Jan Philipp Dobert, Anna Fejtova, Franziska Richter, Melanie Küspert, Philipp Arnold, Paul Saftig, Friederike Zunke
The autophagy-lysosomal pathway is crucial for maintaining homeostasis and survival of neurons, hence defects in this system have been associated with neurodegeneration, including Parkinson's disease (PD). The cysteine proteases cathepsin B (CTSB) and cathepsin L (CTSL) are involved in the clearance of various neurodegenerative disease-related proteins such as amyloid- $$:{upbeta:}$$ , huntingtin and the prion protein. While there are studies implicating CTSB and CTSL as mediators of α-synuclein/SNCA clearance, their exact roles remain unclear. We previously demonstrated that recombinant procathepsin D can enhance the clearance of pathological-aggregates of SNCA both in vitro and in vivo, as well as restoring autophagy function. These results prompted us to investigate the role of the two cysteine proteases CTSB and CTSL regarding SNCA degradation by dosing recombinant human procathepsin B (rHsCTSB) and procathepsin L (rHsCTSL) alone or in combination. We here demonstrate that both proteases are efficiently endocytosed by neuronal cells and transported to lysosomes, where they undergo maturation into active enzymes. Treatment with either rHsCTSB or rHsCTSL resulted in a reduction of different SNCA species, present in Triton-insoluble protein fractions as well as sensitive for various pathology- and structure-specific antibodies analyzed via Western blot, immunofluorescence and ELISA. These effects were found to be similar in all models used here: dopaminergic neurons derived from induced pluripotent stem cells (iPSC) of PD patients harboring the SNCA A53T mutation, ex vivo organotypic brain slices and primary neuronal cultures of human SNCA overexpressing Thy1 mice. Interestingly, our data so far do not indicate a synergistic effect of both cysteine cathepsins when applied together. As proof-of-concept for future therapeutic studies, intracranial injections of both recombinant enzymes reduced SNCA in brains of a transgenic mouse model (Ctsd knockout) harboring SNCA pathology. Moreover, treatment with recombinant CTSB and CTSL improved lysosomal/autophagy functions indicated by recovery of β-glucocerebrosidase (GCase) activity and SQSTM1 (p62) level. Further, SNCA-dependent synaptic defects as well as toxicity was reduced after treatment of neuronal cells. These findings suggest that enhancing lysosomal CTSB or CTSL effectively degrades pathology-associated SNCA, suggesting a potential therapeutic protease-based strategy for PD and other synucleinopathies.
{"title":"Recombinant cathepsins B and L promote α-synuclein clearance and restore lysosomal function in human and murine models with α-synuclein pathology","authors":"Denise Balta, Anish Varghese, Susy Prieto Huarcaya, Alessandro Di Spiezio, André R. A. Marques, Enes Yağız Akdaş, Doğa Tabakacilar, Alice Drobny, Christian Werner, Wei Xiang, Rebecca Mächtel, Jan Philipp Dobert, Anna Fejtova, Franziska Richter, Melanie Küspert, Philipp Arnold, Paul Saftig, Friederike Zunke","doi":"10.1186/s13024-025-00886-1","DOIUrl":"https://doi.org/10.1186/s13024-025-00886-1","url":null,"abstract":"The autophagy-lysosomal pathway is crucial for maintaining homeostasis and survival of neurons, hence defects in this system have been associated with neurodegeneration, including Parkinson's disease (PD). The cysteine proteases cathepsin B (CTSB) and cathepsin L (CTSL) are involved in the clearance of various neurodegenerative disease-related proteins such as amyloid- $$:{upbeta:}$$ , huntingtin and the prion protein. While there are studies implicating CTSB and CTSL as mediators of α-synuclein/SNCA clearance, their exact roles remain unclear. We previously demonstrated that recombinant procathepsin D can enhance the clearance of pathological-aggregates of SNCA both in vitro and in vivo, as well as restoring autophagy function. These results prompted us to investigate the role of the two cysteine proteases CTSB and CTSL regarding SNCA degradation by dosing recombinant human procathepsin B (rHsCTSB) and procathepsin L (rHsCTSL) alone or in combination. We here demonstrate that both proteases are efficiently endocytosed by neuronal cells and transported to lysosomes, where they undergo maturation into active enzymes. Treatment with either rHsCTSB or rHsCTSL resulted in a reduction of different SNCA species, present in Triton-insoluble protein fractions as well as sensitive for various pathology- and structure-specific antibodies analyzed via Western blot, immunofluorescence and ELISA. These effects were found to be similar in all models used here: dopaminergic neurons derived from induced pluripotent stem cells (iPSC) of PD patients harboring the SNCA A53T mutation, ex vivo organotypic brain slices and primary neuronal cultures of human SNCA overexpressing Thy1 mice. Interestingly, our data so far do not indicate a synergistic effect of both cysteine cathepsins when applied together. As proof-of-concept for future therapeutic studies, intracranial injections of both recombinant enzymes reduced SNCA in brains of a transgenic mouse model (Ctsd knockout) harboring SNCA pathology. Moreover, treatment with recombinant CTSB and CTSL improved lysosomal/autophagy functions indicated by recovery of β-glucocerebrosidase (GCase) activity and SQSTM1 (p62) level. Further, SNCA-dependent synaptic defects as well as toxicity was reduced after treatment of neuronal cells. These findings suggest that enhancing lysosomal CTSB or CTSL effectively degrades pathology-associated SNCA, suggesting a potential therapeutic protease-based strategy for PD and other synucleinopathies.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"23 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144915751","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}
Alzheimer’s disease (AD) is the most common type of dementia. Genetic polymorphisms are associated with altered risks of AD onset, pointing to biological processes and potential targets for interventions. Consistent with the important roles of microglia in AD development, genetic mutations of several genes expressed on microglia have been identified as risks for AD. Emerging evidences indicate that the expression of a microglia-specific gene MS4A6A is thought to be associated with AD, since AD patients show upregulation of MS4A6A, and its levels correlate with the severity of clinical neuropathology. However, the mechanism linking MS4A6A and AD has not been experimentally studied. We performed a meta genome-wide association analysis with 734,121 subjects to examine the associations between polymorphisms of MS4A6A with AD risks. In addition, we analyzed the correlation between MS4A6A and AD-related cerebrospinal fluid biomarkers from our own cohort. Furthermore, we for the first time generated a Ms4a6d deficient APP/PS1 model, and systematically examined pathological changes using high-resolution microscopy, biochemistry, and behavioral analysis. We identified several new mutations of MS4A6A with altered AD risks, and discovered specific correlation for some of them with the amount of β-amyloid in cerebrospinal fluid. Protective variant of MS4A6A is associated with elevated expression of the gene. Deficient Ms4a6d led to reduced amyloid clearance in the brain. Immunostaining from postmortem AD patients brain revealed selective expression of MS4A6A in microglia. In APP/PS1 mice lacking Ms4a6d, microglia showed markedly diminished envelopment and phagocytosis of amyloid, leading to increased plaque burden, less compact structure, and more severe synaptic damage. Importantly, Ms4a6d deficiency markedly exacerbated inflammatory responses in both microglia and astrocytes by disinhibiting NF-κB signaling. Overexpressing MS4A6A in human microglia cell line promoted gene expression related to plaque-associated responses and diminished inflammation signatures. Our findings reveal that Ms4a6d deficiency suppresses neuroprotection and worsens neuroinflammation. Sufficient Ms4a6d maybe beneficial for boosting amyloid-related responses and suppressing inflammation in microglia, making it superior than previously reported candidates for microglia modulation. Thus, the elevated MS4A6A levels in AD are likely compensatory and boosting MS4A6A could be an effective treatment.
{"title":"MS4A6A/Ms4a6d deficiency disrupts neuroprotective microglia functions and promotes inflammation in Alzheimer’s disease model","authors":"Hai-Shan Jiao, Yi-Jun Ge, Liang-Yu Huang, Ying Liu, Bang-Sheng Wu, Piao-Piao Lian, Yi-Ning Hao, Shan-Shan Han, Yi-Ting Li, Kai-Min Wu, Chen-Yun Wu, Tian-Lin Cheng, Peng Yuan, Jin-Tai Yu","doi":"10.1186/s13024-025-00887-0","DOIUrl":"https://doi.org/10.1186/s13024-025-00887-0","url":null,"abstract":"Alzheimer’s disease (AD) is the most common type of dementia. Genetic polymorphisms are associated with altered risks of AD onset, pointing to biological processes and potential targets for interventions. Consistent with the important roles of microglia in AD development, genetic mutations of several genes expressed on microglia have been identified as risks for AD. Emerging evidences indicate that the expression of a microglia-specific gene MS4A6A is thought to be associated with AD, since AD patients show upregulation of MS4A6A, and its levels correlate with the severity of clinical neuropathology. However, the mechanism linking MS4A6A and AD has not been experimentally studied. We performed a meta genome-wide association analysis with 734,121 subjects to examine the associations between polymorphisms of MS4A6A with AD risks. In addition, we analyzed the correlation between MS4A6A and AD-related cerebrospinal fluid biomarkers from our own cohort. Furthermore, we for the first time generated a Ms4a6d deficient APP/PS1 model, and systematically examined pathological changes using high-resolution microscopy, biochemistry, and behavioral analysis. We identified several new mutations of MS4A6A with altered AD risks, and discovered specific correlation for some of them with the amount of β-amyloid in cerebrospinal fluid. Protective variant of MS4A6A is associated with elevated expression of the gene. Deficient Ms4a6d led to reduced amyloid clearance in the brain. Immunostaining from postmortem AD patients brain revealed selective expression of MS4A6A in microglia. In APP/PS1 mice lacking Ms4a6d, microglia showed markedly diminished envelopment and phagocytosis of amyloid, leading to increased plaque burden, less compact structure, and more severe synaptic damage. Importantly, Ms4a6d deficiency markedly exacerbated inflammatory responses in both microglia and astrocytes by disinhibiting NF-κB signaling. Overexpressing MS4A6A in human microglia cell line promoted gene expression related to plaque-associated responses and diminished inflammation signatures. Our findings reveal that Ms4a6d deficiency suppresses neuroprotection and worsens neuroinflammation. Sufficient Ms4a6d maybe beneficial for boosting amyloid-related responses and suppressing inflammation in microglia, making it superior than previously reported candidates for microglia modulation. Thus, the elevated MS4A6A levels in AD are likely compensatory and boosting MS4A6A could be an effective treatment.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"11 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144915356","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}
Pub Date : 2025-08-27DOI: 10.1186/s13024-025-00882-5
Yanaika S. Hok-A-Hin, Lisa Vermunt, Carel F.W. Peeters, Emma L. van der Ende, Sterre C.M. de Boer, Lieke H. Meeter, Julie de Houwer, Harro Seelaar, John C. van Swieten, William T. Hu, Alberto Lleó, Daniel Alcolea, Sebastiaan Engelborghs, Anne Sieben, Alice Chen-Plotkin, David J. Irwin, Wiesje M. van der Flier, Yolande A.L. Pijnenburg, Charlotte E. Teunissen, Marta del Campo
Diagnosis of Frontotemporal dementia (FTD) and its specific underlying neuropathologies (frontotemporal lobar degeneration; FTLD-Tau and FTLD-TDP) are challenging, and thus, fluid biomarkers are needed to improve diagnostic accuracy. We used proximity extension assays to analyze 665 proteins in cerebrospinal fluid (CSF) samples from a multicenter cohort, which included patients with FTD (n = 189), Alzheimer’s Disease dementia (AD; n = 232), and cognitively unimpaired individuals (n = 196). In a subset, FTLD neuropathology was determined based on phenotype or genotype (FTLD-Tau = 87 and FTLD-TDP = 67). Differences in protein expression profiles were analyzed using nested linear models. Penalized generalized linear modeling was used to identify classification protein panels, which were translated to custom multiplex assays and validated in two clinical cohorts (cohort 1: n = 161; cohort 2: n = 162), one autopsy-confirmed cohort (n = 100), and one genetic cohort (n = 55). Forty-three proteins were differentially regulated in FTD compared to controls and AD, reflecting axon development, regulation of synapse assembly, and cell-cell adhesion mediator activity pathways. Classification analysis identified a 14- and 13-CSF protein panel that discriminated FTD from controls (FTD diagnostic panel, AUC: 0.96) or AD (FTD differential diagnostic panel, AUC: 0.91). Custom multiplex panels confirmed the strong discriminative performancen between FTD and controls (AUCs > 0.96) and between FTD and AD (AUCs > 0.88) across three validation cohorts, including one with autopsy confirmation (AUCs > 0.90). Validation in genetic FTD (including C9orf72, GRN, and MAPT mutation carriers) revealed high accuracy of the FTD diagnostic panel in identifying both the presymptomatic (AUCs > 0.95) and symptomatic (AUC: 1) stages. Six proteins were differentially regulated between FTLD-TDP and FTLD-Tau. However, a reproducible classification model could not be generated (AUC: 0.80). Overall, this study introduces novel FTD-specific biomarker panels with potential use in diagnostic settings.
{"title":"Large-scale CSF proteome profiling identifies biomarkers for accurate diagnosis of frontotemporal dementia","authors":"Yanaika S. Hok-A-Hin, Lisa Vermunt, Carel F.W. Peeters, Emma L. van der Ende, Sterre C.M. de Boer, Lieke H. Meeter, Julie de Houwer, Harro Seelaar, John C. van Swieten, William T. Hu, Alberto Lleó, Daniel Alcolea, Sebastiaan Engelborghs, Anne Sieben, Alice Chen-Plotkin, David J. Irwin, Wiesje M. van der Flier, Yolande A.L. Pijnenburg, Charlotte E. Teunissen, Marta del Campo","doi":"10.1186/s13024-025-00882-5","DOIUrl":"https://doi.org/10.1186/s13024-025-00882-5","url":null,"abstract":"Diagnosis of Frontotemporal dementia (FTD) and its specific underlying neuropathologies (frontotemporal lobar degeneration; FTLD-Tau and FTLD-TDP) are challenging, and thus, fluid biomarkers are needed to improve diagnostic accuracy. We used proximity extension assays to analyze 665 proteins in cerebrospinal fluid (CSF) samples from a multicenter cohort, which included patients with FTD (n = 189), Alzheimer’s Disease dementia (AD; n = 232), and cognitively unimpaired individuals (n = 196). In a subset, FTLD neuropathology was determined based on phenotype or genotype (FTLD-Tau = 87 and FTLD-TDP = 67). Differences in protein expression profiles were analyzed using nested linear models. Penalized generalized linear modeling was used to identify classification protein panels, which were translated to custom multiplex assays and validated in two clinical cohorts (cohort 1: n = 161; cohort 2: n = 162), one autopsy-confirmed cohort (n = 100), and one genetic cohort (n = 55). Forty-three proteins were differentially regulated in FTD compared to controls and AD, reflecting axon development, regulation of synapse assembly, and cell-cell adhesion mediator activity pathways. Classification analysis identified a 14- and 13-CSF protein panel that discriminated FTD from controls (FTD diagnostic panel, AUC: 0.96) or AD (FTD differential diagnostic panel, AUC: 0.91). Custom multiplex panels confirmed the strong discriminative performancen between FTD and controls (AUCs > 0.96) and between FTD and AD (AUCs > 0.88) across three validation cohorts, including one with autopsy confirmation (AUCs > 0.90). Validation in genetic FTD (including C9orf72, GRN, and MAPT mutation carriers) revealed high accuracy of the FTD diagnostic panel in identifying both the presymptomatic (AUCs > 0.95) and symptomatic (AUC: 1) stages. Six proteins were differentially regulated between FTLD-TDP and FTLD-Tau. However, a reproducible classification model could not be generated (AUC: 0.80). Overall, this study introduces novel FTD-specific biomarker panels with potential use in diagnostic settings.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"24 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144906471","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}
Pub Date : 2025-08-20DOI: 10.1186/s13024-025-00878-1
Lis de Weerd, Selina Hummel, Stephan A Müller, Iñaki Paris, Thomas Sandmann, Marie Eichholtz, Robin Gröger, Amelie L Englert, Stephan Wagner, Connie Ha, Sonnet S Davis, Valerie Warkins, Dan Xia, Brigitte Nuscher, Anna Berghofer, Marvin Reich, Astrid F Feiten, Kai Schlepckow, Michael Willem, Stefan F Lichtenthaler, Joseph W Lewcock, Kathryn M Monroe, Matthias Brendel, Christian Haass
Anti-amyloid β-peptide (Aβ) immunotherapy was developed to reduce amyloid plaque pathology and slow cognitive decline during progression of Alzheimer's disease. Efficient amyloid clearance has been proven in clinical trials testing anti-Aβ antibodies, by their impact on cognitive endpoints correlating with the extent of amyloid removal. However, treatment is associated with adverse side effects, such as oedema and haemorrhages, which are potentially linked to the induced immune response. To improve the safety profile of these molecules, it is imperative to understand the consequences of anti-Aβ antibody treatment on immune cell function. Here, we investigated the effects of long-term chronic anti-Aβ treatment on amyloid plaque pathology and microglial response in the APP-SAA triple knock-in mouse model with an intervention paradigm early during amyloidogenesis. Long-term treatment with anti-Aβ results in a robust and dose-dependent lowering of amyloid plaque pathology, with a higher efficiency for reducing diffuse over dense-core plaque deposition. Analysis of the CSF proteome indicates a reduction of markers for neurodegeneration including Tau and α-Synuclein, as well as immune-cell-related proteins. Bulk RNA-seq revealed a dose-dependent attenuation of disease-associated microglial (DAM) and glycolytic gene expression, which is supported by a parallel decrease of glucose uptake and protein levels of Triggering Receptor Expressed on Myeloid cells 2 (Trem2) protein, a major immune receptor involved in DAM activation of microglia. In contrast, DAM activation around residual plaques remains high, regardless of treatment dose. In addition, microglia surrounding residual plaques display a dose-dependent increase in microglial clustering and a selective increase in antigen-presenting and immune signalling proteins. These findings demonstrate that chronic early intervention by an anti-amyloid immunotherapy leads to a dose-dependent decrease in plaque formation, which is associated with lower brain-wide microglial DAM activation and neurodegeneration. Microglia at residual plaques still display a combined DAM and antigen-presenting phenotype that suggests a continued treatment response.
{"title":"Early intervention anti-Aβ immunotherapy attenuates microglial activation without inducing exhaustion at residual plaques.","authors":"Lis de Weerd, Selina Hummel, Stephan A Müller, Iñaki Paris, Thomas Sandmann, Marie Eichholtz, Robin Gröger, Amelie L Englert, Stephan Wagner, Connie Ha, Sonnet S Davis, Valerie Warkins, Dan Xia, Brigitte Nuscher, Anna Berghofer, Marvin Reich, Astrid F Feiten, Kai Schlepckow, Michael Willem, Stefan F Lichtenthaler, Joseph W Lewcock, Kathryn M Monroe, Matthias Brendel, Christian Haass","doi":"10.1186/s13024-025-00878-1","DOIUrl":"10.1186/s13024-025-00878-1","url":null,"abstract":"<p><p>Anti-amyloid β-peptide (Aβ) immunotherapy was developed to reduce amyloid plaque pathology and slow cognitive decline during progression of Alzheimer's disease. Efficient amyloid clearance has been proven in clinical trials testing anti-Aβ antibodies, by their impact on cognitive endpoints correlating with the extent of amyloid removal. However, treatment is associated with adverse side effects, such as oedema and haemorrhages, which are potentially linked to the induced immune response. To improve the safety profile of these molecules, it is imperative to understand the consequences of anti-Aβ antibody treatment on immune cell function. Here, we investigated the effects of long-term chronic anti-Aβ treatment on amyloid plaque pathology and microglial response in the APP-SAA triple knock-in mouse model with an intervention paradigm early during amyloidogenesis. Long-term treatment with anti-Aβ results in a robust and dose-dependent lowering of amyloid plaque pathology, with a higher efficiency for reducing diffuse over dense-core plaque deposition. Analysis of the CSF proteome indicates a reduction of markers for neurodegeneration including Tau and α-Synuclein, as well as immune-cell-related proteins. Bulk RNA-seq revealed a dose-dependent attenuation of disease-associated microglial (DAM) and glycolytic gene expression, which is supported by a parallel decrease of glucose uptake and protein levels of Triggering Receptor Expressed on Myeloid cells 2 (Trem2) protein, a major immune receptor involved in DAM activation of microglia. In contrast, DAM activation around residual plaques remains high, regardless of treatment dose. In addition, microglia surrounding residual plaques display a dose-dependent increase in microglial clustering and a selective increase in antigen-presenting and immune signalling proteins. These findings demonstrate that chronic early intervention by an anti-amyloid immunotherapy leads to a dose-dependent decrease in plaque formation, which is associated with lower brain-wide microglial DAM activation and neurodegeneration. Microglia at residual plaques still display a combined DAM and antigen-presenting phenotype that suggests a continued treatment response.</p>","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"20 1","pages":"92"},"PeriodicalIF":17.5,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12366171/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144883201","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Lewy body dementia (LBD) is a neurodegenerative disorder characterized by a combination of progressive dementia and spontaneous parkinsonian symptoms. As the second most prevalent form of neurodegenerative dementia after Alzheimer’s disease (AD), LBD necessitates a deeper understanding of its pathogenesis to enable the development of targeted therapeutic interventions. While numerous reviews focus on documenting the clinical manifestations and therapeutic modalities for LBD, animal models provide valuable insights into the underlying mechanisms and potential therapeutic strategies. In this review, we systematically analyze the hallmarks of LBD pathogenesis, genetic risk factors, clinical features, and treatment strategies. Importantly, we emphasize and critically evaluate the pivotal role of animal models in LBD research in advancing our understanding of this disorder, offering a comprehensive framework to elucidate the interactions among misfolded proteins and their role in LBD pathogenesis. Our review proposes new directions for LBD therapeutic management and facilitates the development of innovative pharmacological interventions.
{"title":"Lewy body dementia: exploring biomarkers and pathogenic interactions of amyloid β, tau, and α-synuclein","authors":"Jingfeng Liang, Rongzhen Li, Garry Wong, Xiaobing Huang","doi":"10.1186/s13024-025-00879-0","DOIUrl":"https://doi.org/10.1186/s13024-025-00879-0","url":null,"abstract":"Lewy body dementia (LBD) is a neurodegenerative disorder characterized by a combination of progressive dementia and spontaneous parkinsonian symptoms. As the second most prevalent form of neurodegenerative dementia after Alzheimer’s disease (AD), LBD necessitates a deeper understanding of its pathogenesis to enable the development of targeted therapeutic interventions. While numerous reviews focus on documenting the clinical manifestations and therapeutic modalities for LBD, animal models provide valuable insights into the underlying mechanisms and potential therapeutic strategies. In this review, we systematically analyze the hallmarks of LBD pathogenesis, genetic risk factors, clinical features, and treatment strategies. Importantly, we emphasize and critically evaluate the pivotal role of animal models in LBD research in advancing our understanding of this disorder, offering a comprehensive framework to elucidate the interactions among misfolded proteins and their role in LBD pathogenesis. Our review proposes new directions for LBD therapeutic management and facilitates the development of innovative pharmacological interventions.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"37 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144819215","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}
Pub Date : 2025-08-06DOI: 10.1186/s13024-025-00880-7
Michael T. Maloney, Xiang Wang, Rajarshi Ghosh, Shan V. Andrews, Romeo Maciuca, Shababa T. Masoud, Maayan Agam, Richard M. Caprioli, Giuseppe Astarita, Vitaliy V. Bondar, John Chen, Chi-Lu Chiu, Sonnet S. Davis, Audrey Cheuk-Nga Ho, Hoang N. Nguyen, Nicholas E. Propson, Michelle L. Reyzer, Oliver B. Davis, Matthew C. Deen, Sha Zhu, Gilbert Di Paolo, David J. Vocadlo, Anthony A Estrada, Javier de Vicente, Joseph W. Lewcock, Annie Arguello, Jung H. Suh, Sarah Huntwork-Rodriguez, Anastasia G. Henry
Pathogenic variants in LRRK2 lead to increased kinase activity, and LRRK2 kinase inhibition is being explored in clinical studies as a therapeutic approach for Parkinson’s Disease (PD). LRRK2 inhibitors reduce urine levels of bis(monoacylglycerol)phosphate (BMP), a key endolysosomal lipid involved in glycosphingolipid (GSL) catabolism, in preclinical models and clinical subjects. However, how LRRK2 regulates BMP and its significance with respect to lysosomal dysfunction in PD are poorly defined. Using a combination of genetic and pharmacological approaches to modulate LRRK2 kinase activity, we explored the mechanisms by which LRRK2 can regulate the levels of BMP and PD-relevant GSLs across cellular models, including iPSC-derived microglia, and in tissues and biofluids from mice using mass spectrometry. The impact of LRRK2 activity on various aspects of lysosomal function, including endolysosomal GCase activity, was assessed using live-cell imaging and lysosomal immunoprecipitation. We employed imaging mass-spectrometry and FACS-based methods to specifically examine how LRRK2 modulates BMP and GSL levels across different cell types and regions of the brain. To confirm the relevance of our findings to disease, we measured lysosomal biomarkers in urine and cerebrospinal fluid (CSF) from human subjects carrying variants in LRRK2 associated with PD risk and from subjects dosed with a LRRK2 kinase inhibitor. Our data demonstrate that LRRK2 can employ distinct mechanisms to control intracellular BMP levels and modulate lysosomal homeostasis depending on the tissue examined. We show that LRRK2 deletion or inhibition lowers urine BMP levels by reducing the secretion of BMP-containing vesicles from kidney into urine. In other cell types such as microglia, LRRK2-mediated inhibition of β-glucocerebrosidase (GCase), a PD-linked enzyme involved in GSL catabolism, leads to lysosomal GSL accumulation and increases BMP levels as a compensatory response to restore lysosomal homeostasis. LRRK2 inhibition normalizes lysosomal function and reduces GSL levels in preclinical models and CSF from LRRK2-PD patients. Our study highlights the therapeutic potential of LRRK2 kinase inhibition to improve PD-associated lysosomal dysfunction and supports the utility of GSLs as CSF-based biomarkers of LRRK2 activity. This work includes results from the following phase 1b study in PD patients: ClinicalTrials.gov ID: NCT03710707; https://clinicaltrials.gov/study/NCT03710707?intr=dnl201&rank=2 . The date of registration was 10/18/2018.
{"title":"LRRK2 kinase activity regulates Parkinson’s disease-relevant lipids at the lysosome","authors":"Michael T. Maloney, Xiang Wang, Rajarshi Ghosh, Shan V. Andrews, Romeo Maciuca, Shababa T. Masoud, Maayan Agam, Richard M. Caprioli, Giuseppe Astarita, Vitaliy V. Bondar, John Chen, Chi-Lu Chiu, Sonnet S. Davis, Audrey Cheuk-Nga Ho, Hoang N. Nguyen, Nicholas E. Propson, Michelle L. Reyzer, Oliver B. Davis, Matthew C. Deen, Sha Zhu, Gilbert Di Paolo, David J. Vocadlo, Anthony A Estrada, Javier de Vicente, Joseph W. Lewcock, Annie Arguello, Jung H. Suh, Sarah Huntwork-Rodriguez, Anastasia G. Henry","doi":"10.1186/s13024-025-00880-7","DOIUrl":"https://doi.org/10.1186/s13024-025-00880-7","url":null,"abstract":"Pathogenic variants in LRRK2 lead to increased kinase activity, and LRRK2 kinase inhibition is being explored in clinical studies as a therapeutic approach for Parkinson’s Disease (PD). LRRK2 inhibitors reduce urine levels of bis(monoacylglycerol)phosphate (BMP), a key endolysosomal lipid involved in glycosphingolipid (GSL) catabolism, in preclinical models and clinical subjects. However, how LRRK2 regulates BMP and its significance with respect to lysosomal dysfunction in PD are poorly defined. Using a combination of genetic and pharmacological approaches to modulate LRRK2 kinase activity, we explored the mechanisms by which LRRK2 can regulate the levels of BMP and PD-relevant GSLs across cellular models, including iPSC-derived microglia, and in tissues and biofluids from mice using mass spectrometry. The impact of LRRK2 activity on various aspects of lysosomal function, including endolysosomal GCase activity, was assessed using live-cell imaging and lysosomal immunoprecipitation. We employed imaging mass-spectrometry and FACS-based methods to specifically examine how LRRK2 modulates BMP and GSL levels across different cell types and regions of the brain. To confirm the relevance of our findings to disease, we measured lysosomal biomarkers in urine and cerebrospinal fluid (CSF) from human subjects carrying variants in LRRK2 associated with PD risk and from subjects dosed with a LRRK2 kinase inhibitor. Our data demonstrate that LRRK2 can employ distinct mechanisms to control intracellular BMP levels and modulate lysosomal homeostasis depending on the tissue examined. We show that LRRK2 deletion or inhibition lowers urine BMP levels by reducing the secretion of BMP-containing vesicles from kidney into urine. In other cell types such as microglia, LRRK2-mediated inhibition of β-glucocerebrosidase (GCase), a PD-linked enzyme involved in GSL catabolism, leads to lysosomal GSL accumulation and increases BMP levels as a compensatory response to restore lysosomal homeostasis. LRRK2 inhibition normalizes lysosomal function and reduces GSL levels in preclinical models and CSF from LRRK2-PD patients. Our study highlights the therapeutic potential of LRRK2 kinase inhibition to improve PD-associated lysosomal dysfunction and supports the utility of GSLs as CSF-based biomarkers of LRRK2 activity. This work includes results from the following phase 1b study in PD patients: ClinicalTrials.gov ID: NCT03710707; https://clinicaltrials.gov/study/NCT03710707?intr=dnl201&rank=2 . The date of registration was 10/18/2018.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"12 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144792628","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}
Pub Date : 2025-08-06DOI: 10.1186/s13024-025-00872-7
Heike Hering, Thierry Bussiere, Chia-Chen Liu, Kelly E. Glajch, Andreas Weihofen, Jane Grogan, Dominic M. Walsh
After decades of disappointment, three disease-modifying therapies for Alzheimer’s disease (AD) have been approved since 2021. Burgeoning clinical data on these amyloid β-protein (Aβ) targeting drugs validate the amyloid cascade hypothesis as a molecular roadmap for the development of yet more effective therapeutics and offer a template for drugging other AD-associated aggregation-prone proteins. While there remains much to be learned about the molecular pathology of AD, the current state of knowledge is sufficient to expedite the delivery of new drugs. Mindful of the urgent need of patients, we recommend prioritizing efforts in four directions: finishing the job on Aβ, accelerating and diversifying efforts on tau, and expanding discovery on apolipoprotein E and ⍺-synuclein. For each target, we explain the scientific premise, current efforts, and possible new approaches. In the short- and medium-term, we advocate focusing on the technical innovations required to better drug these already well validated targets. While the focus of this review is on expediating development of monotherapies, the subsequent approval of such agents will enable add-on or combination approaches best suited to individual patients.
{"title":"A manifesto for Alzheimer’s disease drug discovery in the era of disease-modifying therapies","authors":"Heike Hering, Thierry Bussiere, Chia-Chen Liu, Kelly E. Glajch, Andreas Weihofen, Jane Grogan, Dominic M. Walsh","doi":"10.1186/s13024-025-00872-7","DOIUrl":"https://doi.org/10.1186/s13024-025-00872-7","url":null,"abstract":"After decades of disappointment, three disease-modifying therapies for Alzheimer’s disease (AD) have been approved since 2021. Burgeoning clinical data on these amyloid β-protein (Aβ) targeting drugs validate the amyloid cascade hypothesis as a molecular roadmap for the development of yet more effective therapeutics and offer a template for drugging other AD-associated aggregation-prone proteins. While there remains much to be learned about the molecular pathology of AD, the current state of knowledge is sufficient to expedite the delivery of new drugs. Mindful of the urgent need of patients, we recommend prioritizing efforts in four directions: finishing the job on Aβ, accelerating and diversifying efforts on tau, and expanding discovery on apolipoprotein E and ⍺-synuclein. For each target, we explain the scientific premise, current efforts, and possible new approaches. In the short- and medium-term, we advocate focusing on the technical innovations required to better drug these already well validated targets. While the focus of this review is on expediating development of monotherapies, the subsequent approval of such agents will enable add-on or combination approaches best suited to individual patients.\u0000","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"13 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144786533","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}
Pub Date : 2025-08-05DOI: 10.1186/s13024-025-00881-6
Cassia R Overk, Anna Cartier, Gideon Shaked, Edward Rockenstein, Kiren Ubhi, Brian Spencer, Diana L Price, Christina Patrick, Paula Desplats, Eliezer Masliah
Retraction Note
The Editorial team has retracted this article.
After publication, concerns were raised regarding some of the data presented in the figures. Specifically:
Panels Non tg and APP tg in the second row of Fig. 5A appear to overlap;
Panels Non tg in the third rows of Fig. 6B and D appear to overlap;
Panels APP tg and alpha-syn tg in the first row of Fig. 7D appear to overlap;
Panels Non-tg in the second rows of Fig. 7B and D appear to overlap;
Panels APP tg and alpha-syn tg in the third row of Fig. 7D appear to overlap;
Some blots in Fig. 9c appear to have similar bands between the two LV-control groups (vehicle and Aβ1–42).
The authors have stated that these errors occurred during figure preparation. However, due to the number of concerns, the Editors-in-Chief no longer have confidence in the presented data.
Cassia R Overk and Eliezer Masliah disagree with this retraction. The other authors have not responded to any correspondence from the editor or publisher about this retraction.
Authors and Affiliations
Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA
Cassia R Overk, Anna Cartier, Gideon Shaked, Edward Rockenstein, Kiren Ubhi, Brian Spencer, Christina Patrick, Paula Desplats & Eliezer Masliah
Neuropore Therapies, Inc, San Diego, CA, 92121, USA
Diana L Price
Department of Pathology, University of California, San Diego, La Jolla, CA, USA
Eliezer Masliah
Authors
Cassia R OverkView author publications
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Anna CartierView author publications
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Gideon ShakedView author publications
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Edward RockensteinView author publications
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Kiren UbhiView author publications
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Brian SpencerView author publications
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Diana L PriceView author publications
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Christina PatrickView author publications
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Paula DesplatsView author publications
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编辑团队撤回了这篇文章。在发表后，人们对图表中的一些数据提出了担忧。明确:板非tg和应用tg在图5的第二行出现重叠;板非tg在第三排图6 b和D似乎重叠;面板应用tg和alpha-syn tg在图7 D的第一行出现重叠;面板Non-tg第二行图7 b和D似乎重叠;面板应用tg和alpha-syn tg在图7 D的第三行出现重叠;一些污点在图9 c LV-control两组之间似乎也有类似的乐队(车辆和β1-42)。作者指出，这些错误发生在数字准备过程中。但是，由于涉及的问题太多，主编们对所提供的数据不再有信心。Cassia R Overk和Eliezer Masliah不同意这一撤回。其他作者没有回复编辑或出版商关于此次撤稿的任何信件。加州大学圣地亚哥分校神经科学系acassia R Overk， Anna Cartier, Gideon Shaked, Edward Rockenstein, Kiren Ubhi, Brian Spencer, Christina Patrick, Paula Desplats &；Eliezer MasliahNeuropore therapeutics, Inc, San Diego， CA, 92121, USADiana L price，加州大学病理学系，San Diego, La Jolla， CAUSAEliezer MasliahAuthorsCassia R OverkView作者publationssearch author on:PubMed谷歌ScholarAnna CartierView作者publationssearch author on:PubMed谷歌ScholarGideon ShakedView作者publationssearch author on:PubMed谷歌scholarward RockensteinView作者publationssearch author on:PubMed谷歌ScholarKiren UbhiView作者publationssearch author on:PubMed谷歌ScholarBrian SpencerView作者publationssearch author on:PubMed谷歌ScholarDiana L PriceView作者publationssearch author on:PubMed b谷歌ScholarChristina PatrickView作者publationssearch author on:PubMed谷歌ScholarPaula DesplatsView作者publationssearch author on:PubMed谷歌ScholarEliezer MasliahView作者publationssearch author on:PubMed谷歌scholar通讯作者与Eliezer Masliah通信。出版方声明：对于已出版地图的管辖权要求和机构关系，普林格·自然保持中立。开放获取本文遵循知识共享署名4.0国际许可协议，该协议允许以任何媒介或格式使用、共享、改编、分发和复制，只要您适当地注明原作者和来源，提供知识共享许可协议的链接，并注明是否进行了更改。本文中的图像或其他第三方材料包含在文章的知识共享许可协议中，除非在材料的署名中另有说明。如果材料未包含在文章的知识共享许可中，并且您的预期用途不被法律法规允许或超过允许的用途，您将需要直接获得版权所有者的许可。要查看本许可的副本，请访问http://creativecommons.org/licenses/by/4.0/。知识共享公共领域免责条款（http://creativecommons.org/publicdomain/zero/1.0/）适用于本文中提供的数据，除非在数据的署名中另有说明。引用本文overk， c.r., Cartier， A, Shaked， G.等人。注：积累α-突触核蛋白片段的海马神经元细胞更容易通过mGluR5 -对Aβ寡聚物的毒性作用影响路易体痴呆。神经退行性病变，20,87（2025）。https://doi.org/10.1186/s13024-025-00881-6Download citationpublish: 05 August 2025DOI: https://doi.org/10.1186/s13024-025-00881-6Share这篇文章任何你分享了以下链接的人都可以阅读到这篇文章：获取可共享链接对不起，这篇文章目前没有可共享的链接。复制到剪贴板由施普林格自然共享内容倡议提供
{"title":"Retraction Note: Hippocampal neuronal cells that accumulate α-synuclein fragments are more vulnerable to Aβ oligomer toxicity via mGluR5– implications for dementia with lewy bodies","authors":"Cassia R Overk, Anna Cartier, Gideon Shaked, Edward Rockenstein, Kiren Ubhi, Brian Spencer, Diana L Price, Christina Patrick, Paula Desplats, Eliezer Masliah","doi":"10.1186/s13024-025-00881-6","DOIUrl":"https://doi.org/10.1186/s13024-025-00881-6","url":null,"abstract":"<p><b>Retraction Note</b></p><p>The Editorial team has retracted this article.</p><p>After publication, concerns were raised regarding some of the data presented in the figures. Specifically:</p><ul>\u0000<li>\u0000<p>Panels <i>Non tg</i> and <i>APP tg</i> in the second row of Fig. 5A appear to overlap;</p>\u0000</li>\u0000<li>\u0000<p>Panels <i>Non tg</i> in the third rows of Fig. 6B and D appear to overlap;</p>\u0000</li>\u0000<li>\u0000<p>Panels <i>APP tg</i> and <i>alpha-syn tg</i> in the first row of Fig. 7D appear to overlap;</p>\u0000</li>\u0000<li>\u0000<p>Panels <i>Non-tg</i> in the second rows of Fig. 7B and D appear to overlap;</p>\u0000</li>\u0000<li>\u0000<p>Panels <i>APP tg</i> and <i>alpha-syn tg</i> in the third row of Fig. 7D appear to overlap;</p>\u0000</li>\u0000<li>\u0000<p>Some blots in Fig. 9c appear to have similar bands between the two LV-control groups (vehicle and Aβ1–42).</p>\u0000</li>\u0000</ul><p>The authors have stated that these errors occurred during figure preparation. However, due to the number of concerns, the Editors-in-Chief no longer have confidence in the presented data.</p><p>Cassia R Overk and Eliezer Masliah disagree with this retraction. The other authors have not responded to any correspondence from the editor or publisher about this retraction.</p><h3>Authors and Affiliations</h3><ol><li><p>Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA</p><p>Cassia R Overk, Anna Cartier, Gideon Shaked, Edward Rockenstein, Kiren Ubhi, Brian Spencer, Christina Patrick, Paula Desplats & Eliezer Masliah</p></li><li><p>Neuropore Therapies, Inc, San Diego, CA, 92121, USA</p><p>Diana L Price</p></li><li><p>Department of Pathology, University of California, San Diego, La Jolla, CA, USA</p><p>Eliezer Masliah</p></li></ol><span>Authors</span><ol><li><span>Cassia R Overk</span>View author publications<p><span>Search author on:</span><span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Anna Cartier</span>View author publications<p><span>Search author on:</span><span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Gideon Shaked</span>View author publications<p><span>Search author on:</span><span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Edward Rockenstein</span>View author publications<p><span>Search author on:</span><span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Kiren Ubhi</span>View author publications<p><span>Search author on:</span><span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Brian Spencer</span>View author publications<p><span>Search author on:</span><span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Diana L Price</span>View author publications<p><span>Search author on:</span><span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Christina Patrick</span>View author publications<p><span>Search author on:</span><span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Paula Desplats</span>View author publications<p><span>Search author on:</span><span>PubMed<span> <","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"112 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144778200","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}
Pub Date : 2025-07-26DOI: 10.1186/s13024-025-00876-3
Thibaut Burg, Ludo Van Den Bosch
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease affecting the adult motor system, with no effective treatments available. Despite extensive research efforts, the exact pathological cascade leading to progressive motor neuron degeneration remains elusive. Recent evidence highlights significant modifications in lipid metabolism during ALS progression, even before the onset of motor symptoms. Glycerophospholipids, the primary components of cellular membranes, are frequently altered in ALS patients and models. These lipids not only play a structural role in membranes, but also contribute to cellular metabolism, signaling pathways, and cell type-specific processes such as neuronal transmission and muscle contraction. In this review, we discuss glycerophospholipid physiological functions in the motor system and review recent studies demonstrating their alterations and the possible underlying pathological mechanisms in ALS. Furthermore, we discuss challenges emerging from studying lipid alterations in neurodegeneration and evaluate the therapeutic potential of glycerophospholipids.
{"title":"Glycerophospholipids in ALS: insights into disease mechanisms and clinical implication","authors":"Thibaut Burg, Ludo Van Den Bosch","doi":"10.1186/s13024-025-00876-3","DOIUrl":"https://doi.org/10.1186/s13024-025-00876-3","url":null,"abstract":"Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease affecting the adult motor system, with no effective treatments available. Despite extensive research efforts, the exact pathological cascade leading to progressive motor neuron degeneration remains elusive. Recent evidence highlights significant modifications in lipid metabolism during ALS progression, even before the onset of motor symptoms. Glycerophospholipids, the primary components of cellular membranes, are frequently altered in ALS patients and models. These lipids not only play a structural role in membranes, but also contribute to cellular metabolism, signaling pathways, and cell type-specific processes such as neuronal transmission and muscle contraction. In this review, we discuss glycerophospholipid physiological functions in the motor system and review recent studies demonstrating their alterations and the possible underlying pathological mechanisms in ALS. Furthermore, we discuss challenges emerging from studying lipid alterations in neurodegeneration and evaluate the therapeutic potential of glycerophospholipids.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"14 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144710637","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}
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