Molecular Neurodegeneration最新文献

{"title":"The complement cascade in Alzheimer's disease: modern implications of an ancient immune protagonist.","authors":"Maria-Tzousi Papavergi,Praveen Bathini,Brijendra Singh,Cynthia A Lemere","doi":"10.1186/s13024-025-00916-y","DOIUrl":"https://doi.org/10.1186/s13024-025-00916-y","url":null,"abstract":"","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"21 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145759968","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":"Targeted deletion of EMMPRIN in microglia/macrophages mitigates neuronal death in intracerebral hemorrhage.","authors":"Zhe Li,Xiangyu Zhang,Maryam Mobarakabadi,Yang Liu,Ruixue Wei,Claudia Silva,Frank Visser,Antoine Dufour,Daniel Young,Deepak Kaushik,V Wee Yong,Mengzhou Xue","doi":"10.1186/s13024-025-00917-x","DOIUrl":"https://doi.org/10.1186/s13024-025-00917-x","url":null,"abstract":"","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"232 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145746707","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 pesticide chlorpyrifos increases the risk of Parkinson's disease.","authors":"Kazi Md Mahmudul Hasan, Lisa M Barnhill, Kimberly C Paul, Chao Peng, William Zeiger, Beate Ritz, Marisol Arellano, Michael Ajnassian, Shujing Zhang, Aye Theint Theint, Gazmend Elezi, Hilli Weinberger, Julian P Whitelegge, Qing Bai, Sharon Li, Edward A Burton, Jeff M Bronstein","doi":"10.1186/s13024-025-00915-z","DOIUrl":"10.1186/s13024-025-00915-z","url":null,"abstract":"<p><p>BACKGROUND: Pesticides as a class have been associated with an increased risk of Parkinson’s disease (PD), but it is unclear which specific pesticides contribute to this association and whether it is causal. Since chlorpyrifos (CPF) exposure has been implicated as a risk factor for PD, we investigated its association to incident PD and if this association is biologically plausible using human, rodent, and zebrafish (ZF) studies. METHODS: The association of CPF with PD was performed using the UCLA PEG cohort (829 PD and 824 control subjects), the pesticide use report and geocoding the residence and work locations to estimate exposures. For the mammalian studies, 6 months old male mice were exposed to CPF by inhalation (consistent with human exposures) for 11 weeks and behavioral and stereological pathological analyses were performed. Transgenic ZF were utilized to determine the mechanism of CPF neurotoxicity. RESULTS: Long-term residential exposure to CPF was associated with more than a 2.5-fold increased risk of developing PD. Mice exposed to aerosolized CPF developed motor impairment, dopaminergic neuron loss, microglial activation, and an increase in pathological α-synuclein (α-syn). Using ZF, we found that CPF-induced dopaminergic neuron loss was at least partially due to autophagy dysfunction and synuclein accumulation, as knocking down LC3 recapitulated the dopaminergic neuron loss and restoring autophagic flux or eliminating synuclein reduced neuronal vulnerability. CONCLUSIONS: CPF exposure is associated with an increased risk of developing PD and relevant exposures in animal models establish biological plausibility. In addition to establishing a new risk factor for PD, we identified new therapeutic targets for disease modification.</p>","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":" ","pages":"3"},"PeriodicalIF":19.6,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12801438/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145743366","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}

{"title":"Diagnostic biomarkers for α-synucleinopathies- state of the art and future developments: a systematic review.","authors":"V Donadio,M Ingelsson,G Rizzo,A Furia,A Incensi,C Delprete,M Pinho,R Liguori,S Pritzkow","doi":"10.1186/s13024-025-00914-0","DOIUrl":"https://doi.org/10.1186/s13024-025-00914-0","url":null,"abstract":"","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"204 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145674411","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":"DAP12 deletion reduces neuronal SLIT2 and demyelination and enhances brain resilience in female tauopathy mice.","authors":"Hao Chen,Li Fan,Qi Guo,Man Ying Wong,Jingjie Zhu,Nessa Foxe,Winston Wang,Aviram Nessim,Gillian Carling,Bangyan Liu,Chloe Lopez-Lee,Yige Huang,Sadaf Amin,Tark Patel,Sue-Ann Mok,Won-Min Song,Bin Zhang,Shiaoching Gong,Qin Ma,Hongjun Fu,Li Gan,Wenjie Luo","doi":"10.1186/s13024-025-00903-3","DOIUrl":"https://doi.org/10.1186/s13024-025-00903-3","url":null,"abstract":"BACKGROUNDPathogenic tau accumulation drives neurodegeneration in Alzheimer's disease (AD). Enhancing the aging brain's resilience to tau pathology would lead to novel therapeutic strategies. DAP12 (DNAX-activation protein 12), highly and selectively expressed by microglia, plays a crucial role in microglial immune responses. Previous studies have shown that tauopathy mice lacking DAP12 exhibit higher tau pathology but are protected from tau pathology-induced cognitive deficits. However, the exact mechanism behind this resilience remains elusive.METHODSWe investigated the effects of DAP12 deletion on tau pathology, as well as tau-induced brain inflammation and neurodegeneration, in homozygous human Tau P301S transgenic mice. In addition, we conducted single-nucleus RNA sequencing of hippocampal tissues to examine cell type-specific transcriptomic changes at the single-cell level. Furthermore, we utilized the CellChat package to profile cell-cell communication in the mouse brain and investigated how these interactions are affected by tau pathology and Dap12 deletion.RESULTSWe demonstrated that Dap12 deletion reduced tau processing in primary microglia and increased tau pathology in female tauopathy mice, with minimal effects on males. Despite this, Dap12 deletion markedly reduced brain inflammation, synapse loss, and demyelination, indicating enhanced resilience to tau toxicity. Single-cell transcriptomic profiling revealed that Dap12 deletion blocked tau-induced alterations in microglia, neurons, and oligodendrocytes. CellChat analysis identified aberrant tau-induced SLIT2 signaling from excitatory neurons to oligodendrocytes. Dap12 deletion suppressed Slit2 upregulation and mitigated demyelination, while lentiviral-Slit2 overexpression induced myelin loss in tauopathy mice. Elevated SLIT2 levels were associated with demyelination in tauopathy mouse model and human AD brains. Spatial transcriptomics revealed a spatial correlation of SLIT2 expression and tau pathology in AD brain tissue.CONCLUSIONSOur study identifies a novel DAP12-dependent mechanistic link between upregulated Slit2 expression in excitatory neurons and oligodendrocyte-dependent myelination loss in tauopathy. Despite elevating tau load, the absence of microglial Dap12 ameliorates neuroinflammation and improves brain functions in tauopathy mice. Our study suggests that selectively targeting the toxic aspects of DAP12 signaling while preserving its beneficial functions may be a promising strategy to enhance brain resilience in AD.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"198200 1","pages":"124"},"PeriodicalIF":15.1,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145657083","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":"Pioglitazone modulates metabolic adaptation and peripheral nerve regeneration after injury.","authors":"Antonia Seitz, Taylan Özöncü, Daniela Sinske, Claudia Klugmann, Daniel Tews, Pamela Fischer-Posovszky, Bernd Knöll, Sofia Meyer Zu Reckendorf","doi":"10.1186/s13024-025-00913-1","DOIUrl":"10.1186/s13024-025-00913-1","url":null,"abstract":"<p><p>Peripheral nerves have an intrinsic capacity for regeneration after traumatic injury, with Schwann cells (SCs) playing a central role in orchestrating this complex process. Critical components of successful regeneration include SC reprogramming into repair SCs, debris removal and metabolic adaptations. Up to now, there are no pharmacological treatments available in the clinics to improve nerve regeneration. In this study, we investigated peroxisome proliferator-activated receptor gamma (PPARɣ) as a therapeutic target in the context of nerve regeneration, since we previously found this transcription factor to be involved in SC reprograming and metabolic adaptations. Therefore, we used a mouse model of sciatic nerve crush injury and applied the PPARɣ agonist pioglitazone (PIO) in two different treatment paradigms: (i) acutely after injury (0-5 days post injury) and (ii) delayed (5-21 days post injury), thereby addressing different phases of regeneration. Our findings revealed that PIO treatment immediately following nerve injury (first treatment paradigm) disrupted SC transition into the repair phenotype and diminished the physiological inflammatory response. As a consequence, axonal and myelin debris clearance was delayed, ultimately resulting in impaired axonal outgrowth and nerve regeneration. In the second treatment paradigm (PIO administration starting five days after injury) SCs had already acquired the repair phenotype and immune cell infiltration had taken place when PIO administration started. There, PIO promoted axonal regeneration, enhanced remyelination, and improved functional recovery. Importantly, PIO treatment increased mitochondrial content in neurons and SCs. In addition, delayed application of PIO induced lipid metabolism, glycolysis and ATP production in SCs, leading to the assumption that improved metabolic conditions mediate enhanced nerve regeneration in this treatment paradigm. These findings show that depending on the timing of PIO treatment, PPARɣ can serve as a potential therapeutic agent to improve nerve regeneration by promoting key metabolic adaptations.</p>","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"20 1","pages":"123"},"PeriodicalIF":19.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12670764/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145654813","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}

{"title":"Domain mapping of disease mutations reveals pathogenic SORL1 variants in Alzheimer's disease.","authors":"Olav M Andersen, Matthijs W J de Waal, Giulia Monti, Niccolo Tesi, Anne Mette G Jensen, Christa de Geus, Rosalina van Spaendonk, Maartje Vogel, Shahzad Ahmad, Najaf Amin, Philippe Amouyel, Gary W Beecham, Céline Bellenguez, Claudine Berr, Joshua C Bis, Anne Boland, Paola Bossù, Femke Bouwman, Jose Bras, Camille Charbonnier, Jordi Clarimon, Carlos Cruchaga, Antonio Daniele, Jean-François Dartigues, Stéphanie Debette, Jean-François Deleuze, Nicola Denning, Anita L DeStefano, Oriol Dols-Icardo, Cornelia M van Duijn, Lindsay A Farrer, Maria Victoria Fernández, Wiesje M van der Flier, Nick C Fox, Daniela Galimberti, Emmanuelle Genin, Johan J P Gille, Benjamin Grenier-Boley, Detelina Grozeva, Yann Le Guen, Rita Guerreiro, Jonathan L Haines, Clive Holmes, Holger Hummerich, M Arfan Ikram, M Kamran Ikram, Amit Kawalia, Robert Kraaij, Jean-Charles Lambert, Marc Lathrop, Afina W Lemstra, Alberto Lleó, Richard M Myers, Marcel M A M Mannens, Rachel Marshall, Eden R Martin, Carlo Masullo, Richard Mayeux, Simon Mead, Patrizia Mecocci, Alun Meggy, Merel O Mol, Benedetta Nacmias, Adam C Naj, Valerio Napolioni, J Nicholas Cochran, Gaël Nicolas, Florence Pasquier, Pau Pastor, Margaret A Pericak-Vance, Yolande A L Pijnenburg, Fabrizio Piras, Olivier Quenez, Alfredo Ramirez, Rachel Raybould, Richard Redon, Marcel J T Reinders, Anne-Claire Richard, Steffi G Riedel-Heller, Fernando Rivadeneira, Jeroen G J van Rooij, Stéphane Rousseau, Natalie S Ryan, Pascual Sanchez-Juan, Gerard D Schellenberg, Philip Scheltens, Jonathan M Schott, Sudha Seshadri, Daoud Sie, Rebecca Sims, Erik A Sistermans, Sandro Sorbi, John C van Swieten, Betty Tijms, André G Uitterlinden, Pieter Jelle Visser, Michael Wagner, David Wallon, Li-San Wang, Julie Williams, Jennifer S Yokoyama, Aline Zarea, Sven J van der Lee, Johan G Olsen, Marc Hulsman, Henne Holstege","doi":"10.1186/s13024-025-00907-z","DOIUrl":"10.1186/s13024-025-00907-z","url":null,"abstract":"<p><p>BACKGROUND: Protein truncating variants (PTVs) in SORL1 are observed almost exclusively in Alzheimer’s Disease (AD) cases, but the effect of rare SORL1 missense variants is unclear. METHODS: To identify high-priority missense variants (HPVs), we applied ‘domain mapping of disease mutations’ for the 637 unique coding SORL1 variants detected in 18,959 AD-cases and 21,893 non-demented controls. RESULTS: In this sample, PTVs and HPVs associated with respectively a 35- and 10-fold increased risk of early onset AD and 17- and 6-fold increased risk of overall AD. The median age at onset (AAO) of PTV- and HPV-carriers was 62 and 64 years, and APOE-genotype contributed to AAO-variability. The median AAO of PTV- and HPV-carriers is ~8–10 years earlier than wild-type SORL1 carriers, matched for APOE-genotype. Specific HPVs are highly penetrant and lead to earlier AAOs than PTVs, suggesting possible dominant negative effects. CONCLUSION: Our results justify a debate on whether HPV carriers should be considered for clinical counseling.</p>","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"20 1","pages":"122"},"PeriodicalIF":19.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12667055/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145654854","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}

{"title":"Multidomain therapy for Alzheimer’s disease: a scoping review of cognitive decline trials","authors":"Jared C. Roach, Gwênlyn Glusman, Molly K. Rapozo, David A. Merrill, Jennifer Bramen, John F. Hodes, Prabha Siddarth, Somayeh Meysami, Shannel H. K. Elhelou, Ryan M. Glatt, Lance Edens, Cory Funk, Dan Kelly, William R. Shankle, Dale Bredesen, Cyrus A. Raji, Leroy Hood","doi":"10.1186/s13024-025-00912-2","DOIUrl":"https://doi.org/10.1186/s13024-025-00912-2","url":null,"abstract":"Alzheimer’s disease (AD) leading to cognitive decline and dementia results from the interplay of multiple interacting dysfunctional biological systems. These systems can be categorized by domain, such as inflammation, cardiovascular health, proteostasis, or metabolism. Specific causes of AD differ between individuals, but each individual is likely to have causes stemming from multiple domains. Personalized multidomain therapy has been proposed as a standard of care for AD. We sought to enumerate and describe prospective randomized controlled trials (RCTs) for multidomain interventions for AD, and to extract their inclusion criteria, trial design parameters (length, number of participants), and outcome measures. We sought to clarify gaps and opportunities in research and clinical translation. We conducted a scoping review using the standardized PRISMA-ScR methodological framework. We include all cohort studies and RCTs for multidomain (also known as multimodal, multicomponent, multidimensional, or multisystem) therapy of any stage of AD, published for all dates through July 28, 2025. There have been 23 studies (completed or reported as ongoing) of multidomain interventions for AD, including 19 RCTs. Of the 15 completed RCTs, 12 demonstrate benefit from their intervention in at least one arm. Although these RCTs differ widely in their parameters, the majority support the use of multidomain therapy, and show effect sizes greater than reported for unimodal therapies, including pharmaceuticals. Multidomain therapy should be the standard of care for AD. Multidomain interventions (also known as treatments) should be employed widely, early, and first-line. Treatment or prevention is likely to be most effective at early, presymptomatic stages, but is worthwhile at all stages of disease. In order to influence multiple domains, multiple modes of therapy are likely necessary in all patients. Some individual modes, such as particular lifestyle interventions, may target multiple domains. Nevertheless, most patients will benefit from multiple modes of intervention (multimodal intervention) that together target multiple domains. Standard-of-care guidelines should explicitly include multidomain interventions. Future clinical trials must be designed to iteratively improve multidomain therapies. Payors should embrace reimbursement for effective multidomain intervention, including personalized coaching.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"20 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145568011","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":"Death-associated protein kinase 1-dependent SENP1 degradation increases tau SUMOylation and leads to cognitive dysfunction in a mouse model for tauopathy","authors":"Xindong Shui, Xiaoqing Zheng, Jinfeng Wu, Mi Zhang, Gamin Kim, Renxuan Chen, Lianlian Peng, Zonghai Wang, Yameng Zheng, Ling Zhang, Ruomeng Li, Long Wang, Ying Zhou, Jungho Kim, Dongmei Chen, Tao Zhang, Tae Ho Lee","doi":"10.1186/s13024-025-00911-3","DOIUrl":"https://doi.org/10.1186/s13024-025-00911-3","url":null,"abstract":"Emerging evidence implicates that tau SUMOylation disrupts tau homeostasis. Death-associated protein kinase 1 (DAPK1) has been shown to affect tau phosphorylation and accumulation. The sentrin-specific protease 1 (SENP1) is important for protein SUMOylation, and is a potential substrate of DAPK1. However, whether DAPK1 regulates tau SUMOylation and proteostasis through modulating SENP1 remains elusive. We identified the phosphorylation of SENP1 by DAPK1 using in vitro kinase assay and mass spectrometry. The influence of DAPK1 on SENP1 expression, tau SUMOylation and phosphorylation was analyzed using a mouse model for tauopathy by overexpressing human tau in the hippocampal CA3 region, as well as using human AD brain tissues. DAPK1 genetic ablation or pharmacological inhibition was applied to assess the impact of DAPK1 on tau accumulation-related pathologies including synaptic dysfunction and gliosis. The cognitive and emotional functions were evaluated using Y-maze, novel object recognition test, Morris water maze, open field test, and elevated plus maze. DAPK1 directly interacts with and phosphorylates SENP1, leading to SENP1 degradation via the ubiquitin-proteasome pathway. DAPK1 promotes tau SUMOylation by suppressing SENP1 expression in neurons. DAPK1 downregulation or pharmacological inhibition restores SENP1 level and reduces tau SUMOylation, resulting in an attenuation of aberrant tau phosphorylation and accumulation, which ultimately contributes to improved cognitive ability in vivo. We show that DAPK1 expression is negatively correlated with SENP1 level in human AD hippocampal tissues. DAPK1-mediated SENP1 phosphorylation and degradation promote tau SUMOylation, exacerbating tau pathology and cognitive dysfunction in tauopathy. Our findings highlight the DAPK1-SENP1-tau SUMOylation axis as a critical regulator of tau homeostasis, and establish DAPK1 inhibition as a promising therapeutic strategy for AD and related tauopathies.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"24 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145559349","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":"High-sensitivity plasma proteomics reveals disease-specific signatures and predictive biomarkers of Alzheimer’s disease phenotypes in a large mixed-dementia cohort","authors":"Katherine Gong, Jigyasha Timsina, Muhammad Ali, Yike Chen, Menghan Liu, Ciyang Wang, Cyril Pottier, Geoffrey K. Feld, Gyujin Heo, Tammie L. S. Benzinger, Cyrus A. Raji, Beau Ances, Brian A. Gordon, Julie K. Wisch, Suzanne E. Schindler, John C. Morris, David M. Holtzman, Laura Ibanez, Carlos Cruchaga","doi":"10.1186/s13024-025-00909-x","DOIUrl":"https://doi.org/10.1186/s13024-025-00909-x","url":null,"abstract":"Novel plasma assays enabled accurate blood-based biomarkers for neurodegenerative diseases with minimally invasive options for clinical use. Large-scale studies encompassing multiple neurodegenerative diseases using novel multiplex platforms are essential to uncover disease-specific biomarkers and pathways. We generated and analyzed plasma biomarker data using the NULISAseq™ CNS Panel from 3,232 participants with Alzheimer disease (AD), Dementia with Lewy bodies (DLB), Frontotemporal dementia (FTD), Parkinson disease (PD) and cognitively unimpaired individuals, from the Charles F. and Joanne Knight Alzheimer Disease Research Center. We identified proteins associated with disease status and AD-related phenotypes (Clinical Dementia Rating®, CSF Aβ42/Aβ40, Amyloid-PET, and Tau-PET). These proteins were used to identify disease-specific biomarkers and perform pathway analyses. We identified 81 proteins associated with AD, 21 with DLB, four with FTD, and 52 with PD after multiple test correction. Disease comparison showed that PD and DLB had the highest similarity, followed by AD and DLB. Concurrently, each disease also presented disease-specific signatures. Some AD-specific proteins included p-tau217; MSLN and SAA1 were specific to DLB, and FLT1 and PARK7 to PD. We also identified eight proteins associated with Amyloid-PET, eight with Tau-PET, 14 with CSF Aβ42/40 ratio, and 72 with CDR, some of which were specific to each phenotype. We used a data-driven approach to identify the p-tau217 cut-off for biomarker positivity. Plasma p-tau217 achieved an AUC of 0.81 (95% CI: 0.79–0.83) for AD diagnosis and 0.96 (95% CI: 0.94–0.98) for Amyloid positivity. P-tau217 had 93.77% agreement with Amyloid-PET status. Proteins associated with AD were enriched in protein-lipid complex binding pathway, whereas PD associated proteins were enriched in laminin-related pathways. FTD associated proteins were enriched in cytoskeleton proteins. This is the largest plasma NULISA CNS study performed till date and covers the four major neurodegenerative diseases: AD, PD, DLB and FTD. We validated the high classification accuracy of the NULISA plasma p-tau217 and its strong correlation with Amyloid-PET status. We also identified disease-specific proteins that could enhance differential diagnosis. These findings highlight the potential of the NULISA platform as a reliable quantitative tool for research and clinical applications in neurodegenerative diseases.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"6 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145535283","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}