Molecular Neurodegeneration最新文献

{"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":"","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"20 1","pages":"122"},"PeriodicalIF":17.5,"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}

{"title":"Plasma TDP-43 is a potential biomarker for advanced limbic-predominant age-related TDP-43 encephalopathy neuropathologic change","authors":"Jijing Wang, Julie A. Schneider, David A. Bennett, Nicholas T. Seyfried, Tracy L. Young-Pearse, Hyun-Sik Yang","doi":"10.1186/s13024-025-00910-4","DOIUrl":"https://doi.org/10.1186/s13024-025-00910-4","url":null,"abstract":"<p>Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) is a major cause of late-onset amnestic dementia, yet no diagnostic biomarker is available [1]. The recently published clinical criteria operationally defined “probable LATE” in older individuals with negative Alzheimer’s disease (AD) biomarkers [2]. However, most LATE-NC cases are comorbid with Alzheimer’s disease neuropathologic change (ADNC), and in vivo diagnosis of LATE-NC remains challenging without a specific molecular biomarker [2]. Prior plasma biomarker investigations of other TDP-43 proteinopathies, such as frontotemporal lobar degeneration or amyotrophic lateral sclerosis (ALS), using various TDP-43 immunoassays have shown conflicting results [3]. Measuring peripheral extracellular vesicles (EV) TDP-43 has shown initial promise [4], but EV-based methods are currently limited. Recently, plasma phospho-TDP-43 (pTDP-43) measured with a highly sensitive Nucleic Acid Linked Immuno-Sandwich Assay (NULISA) has been shown to be elevated in ALS [5], and another study showed an association between NULISA-measured plasma pTDP-43 with findings suggestive of underlying LATE-NC (hippocampal atrophy and cognitive decline) [6]. Here, we examine the biomarker potential of plasma TDP-43 measured with NULISA in detecting advanced LATE-NC.</p><p>We analyzed the data from fifty deceased participants from an extensively characterized clinical-pathologic cohort—the Religious Orders Study and the Rush Memory and Aging Project [7] (ROSMAP; <i>N</i> = 18 no/low ADNC cognitively unimpaired controls [“controls”], <i>N</i> = 32 dementia with significant ADNC [“AD”]; Table S1)—who also had plasma NULISA data [8]. LATE-NC stages were documented as follows: stage 0 = none, stage 1 = amygdala only, stage 2 = involving hippocampus/entorhinal cortex, and stage 3 = involving neocortex. We focused on detecting LATE-NC stages 2 and 3 (“advanced LATE-NC”), which are associated with clinically significant cognitive dysfunction [1]. Brain LATE-NC burden was assessed by averaging a 6-point scale TDP-43 cytoplasmic inclusion burden across six brain regions (amygdala, hippocampus CA1/subiculum, dentate gyrus, entorhinal cortex, middle temporal cortex, and midfrontal cortex) [9]. The quantitative amyloid β (Aβ) and tau burden in the brain was measured by immunohistochemistry in eight regions: hippocampus, entorhinal cortex, midfrontal cortex, inferior temporal cortex, angular gyrus, calcarine cortex, anterior cingulate cortex, and superior frontal cortex. Neocortical Lewy body (present/absent), which is associated with cognitive decline, was assessed with α-synuclein immunostaining. Hippocampal sclerosis (HS; severe neuronal loss and gliosis in the CA1/subiculum) was recorded as present/absent. Plasma samples, average 3.8 ± 1.9 years before death, were analyzed using the NULISA CNS Disease Panel (Alamar Biosciences). Data were normalized to internal control and inter-plate control values, lo","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"11 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145509655","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":"M102 activates both NRF2 and HSF1 transcription factor pathways and is neuroprotective in cell and animal models of amyotrophic lateral sclerosis","authors":"Amy F. Keerie, Raquel Rua Martins, Chloe F. Allen, Katie Bowden, Sufana Al Mashhadi, Thomas Marlow, Monika Myszczynska, Nikitha Thakur, Selina N. Beal, Allan Shaw, Shivani Suresh, Scott N. McKinnon, Johnathan Cooper-Knock, Ryan J. H. West, Sam Bonsall, Alex Daniel, Tyler Wells, Vedanth Kumar, Brittany C. S. Ellis, Maureen Higgins, Albena T. Dinkova-Kostova, Tatyana A. Shelkovnikova, Ira N. Kalfus, Ning Shan, Pamela J. Shaw, Laura Ferraiuolo, Richard J. Mead","doi":"10.1186/s13024-025-00908-y","DOIUrl":"https://doi.org/10.1186/s13024-025-00908-y","url":null,"abstract":"M102 is a central nervous system (CNS) penetrant small molecule electrophile which activates in vivo the NF-E2 p45-related factor 2-antioxidant response element (NRF2-ARE) pathway, as well as transcription of heat-shock element (HSE) associated genes. In the TDP-43Q331K transgenic mouse model of ALS dosed subcutaneously at 5 mg/kg OD or 2.5 mg/kg BD with M102, significant improvements in compound muscle action potential (CMAP) amplitude of hind limb muscles and gait parameters were observed at 6 months of age, with associated target engagement. An oral dose response study of M102 in SOD1G93A transgenic mice showed a dose-dependent improvement in CMAP of hindlimb muscles which correlated with preservation of lumbar spinal motor neurons at the same time point. These data enabled prediction of human efficacious exposures and doses, which were well within the safety margin predicted from Good Laboratory Practice (GLP) toxicology studies. A parallel program of work in vitro showed that M102 rescued motor neuron survival in co-culture with patient-derived astrocytes from sporadic, C9orf72 and SOD1 ALS cases. Markers of oxidative stress, as well as indices of TDP-43 proteinopathy were also reduced by exposure to M102 in these in vitro models. This comprehensive package of preclinical efficacy data across two mouse models as well as patient-derived astrocyte toxicity assays, provides a strong rationale for clinical evaluation of M102 in ALS patients. Combined with the development of target engagement biomarkers and the completed preclinical toxicology package, a clear translational pathway to testing in ALS patients has been developed.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"65 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145435097","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":"Neuropathology of Lewy body dementia: Lewy-related pathology, α-synuclein oligomers, and comorbid pathologies","authors":"Hiroaki Sekiya, Tomoyasu Matsubara, Michael A. DeTure, Dennis W. Dickson","doi":"10.1186/s13024-025-00900-6","DOIUrl":"https://doi.org/10.1186/s13024-025-00900-6","url":null,"abstract":"Lewy body dementia is the second most common form of neurodegenerative dementia, following Alzheimer’s disease. This umbrella term encompasses dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD). The distinction between these two conditions lies in the timing of the onset of cognitive impairment relative to motor symptoms. In DLB, cognitive impairment precedes or coincides with motor symptoms within the first year, whereas in PDD, cognitive decline occurs more than a year after the onset of motor symptoms. Clinically, in addition to cognitive decline, patients with Lewy body dementia have parkinsonism, visual hallucinations, and fluctuations of cognitive status. The pathological hallmark of this condition is the presence of Lewy bodies and Lewy neurites, collectively referred to as Lewy-related pathology. This is identical to Parkinson’s disease, where dementia is not observed. The principal component of Lewy-related pathology is α-synuclein, which classifies this disorder as an α-synucleinopathy. While Lewy-related pathology represents a later stage of α-synuclein aggregation, earlier stages involve α-synuclein oligomers. Emerging evidence suggests α-synuclein oligomers may be more toxic than Lewy-related pathology. In addition to α-synuclein pathology, previous studies frequently observed comorbid pathological conditions, including Alzheimer’s disease neuropathologic change, TAR DNA-binding protein 43 (TDP-43) pathology, and cerebral small vessel disease among others. In this review, we provide a comprehensive overview of the underlying pathologies for Lewy body dementia and their molecular mechanisms and clinical implications. We also discuss concepts including the prion-like propagation hypothesis of α-synuclein, α-synuclein strain hypothesis, and recent advances in machine learning algorithms for analyzing propagation patterns. The purpose of this manuscript is to elucidate these complex pathological conditions, advance our understanding of the disease, and improve diagnostic strategies.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"36 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145427612","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":"C-terminus-dependent detection of lysosomal alpha-synuclein in nigral Parkinson’s disease human brain neurons","authors":"Martino L. Morella, Bana Al Khayrat, Tim E. Moors, Lisanne in’t Veld, Irene Frigerio, Vinod Udayar, Bram L. van der Gaag, Wilma D. J. van de Berg","doi":"10.1186/s13024-025-00884-3","DOIUrl":"https://doi.org/10.1186/s13024-025-00884-3","url":null,"abstract":"The abnormal accumulation of alpha-Synuclein (αSyn) within neurons is a hallmark of synucleinopathies, such as Parkinson's disease (PD), and could stem from impaired protein degradation. Genetic, in vitro, and post-mortem studies have suggested that lysosomal dysfunction and impaired proteolytic activity play important roles in the pathogenesis of PD. Lysosomes have been proposed as key sites for αSyn degradation, but direct evidence of the lysosomal localization of endogenous αSyn in the human brain is limited. This study aimed to investigate the localization of αSyn proteoforms, including different post-translational modifications (PTMs), within lysosomes of post-mortem human nigral neurons. We analyzed formalin-fixed, paraffin-embedded brain tissue from donors diagnosed with PD, PD with Dementia (PDD) or incidental Lewy body disease (iLBD). Substantia nigra sections were assessed using an extensive panel of αSyn-specific antibodies, including PTM-specific antibodies, and selected lysosomal markers via multiplex immunofluorescence, confocal and stimulated emission depletion (STED) microscopy. Here, we demonstrate widespread accumulation of αSyn within lysosomes in nigral dopaminergic neuron somas of donors with PD/PDD and iLBD. This lysosomal αSyn appeared morphologically distinct from cytosolic inclusions such as Lewy bodies (LBs) and related macro-aggregates, and was present both in cells with and without these larger αSyn deposits. When present, macro-aggregates were consistently accompanied by ring-shaped lysosomal structures. Compared to other neuronal morphologies, lysosomal αSyn was the most frequent morphology at early Braak stages (1–4), with a decline at later stages (5–6). Interestingly, lysosomal αSyn was detected solely by targeting the N-terminus or the NAC domain of αSyn, and not with antibodies targeting Serine 129-phosphorylated αSyn or other epitopes at the C-terminus (CT), suggesting that lysosome-associated αSyn lacks the CT. Our findings reveal two co-existing pools of neuronal somatic αSyn: a CT-negative lysosome-associated form, and a primarily non-lysosomal CT-positive form. Overall, we provide direct evidence of lysosomal involvement in cellular αSyn metabolism in post-mortem human PD brain.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"68 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145405150","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":"Interplay between astrocyte reactivity and APOE ε4 status is associated with accelerated pTau-related tau pathology in Alzheimer’s disease","authors":"Xiaoxie Mao, Yan Wang, Ying Luan, Ying Wang, Jie Wang, Wenlin Dai, Yihui Guan, Qi Huang, Roger N. Gunn, Rik Ossenkoppele, Binyin Li, Zijing Li, Qihao Guo, Fang Xie","doi":"10.1186/s13024-025-00906-0","DOIUrl":"https://doi.org/10.1186/s13024-025-00906-0","url":null,"abstract":"Various plasma phosphorylated tau species have been shown to be associated with amyloid-β (Aβ) PET and Tau PET in Alzheimer’s disease (AD), but whether APOE ε4 affects the interaction between glial fibrillary acidic protein (GFAP) and phosphorylated tau (pTau), and whether a three-way interaction exists among APOE ε4, GFAP, and pTau that influences AD progression remain unclear. The study included 563 participants from the Chinese Preclinical Alzheimer’s Disease Study (CPAS) and 243 from Alzheimer’s Disease Neuroimaging Initiative (ADNI), all of whom underwent Aβ PET, magnetic resonance imaging (MRI), neuropsychological assessments, and plasma biomarker analyses (GFAP, pTau181, pTau231, pTau217), with subsets undergoing Tau PET. The longitudinal data of 101 participants from ADNI were additionally included. We employed linear regression models with interaction terms to examine how APOE ε4 status and plasma GFAP levels modulate the relationships between plasma pTau biomarkers and AD pathology cross-sectionally and longitudinally. Plasma GFAP and pTau biomarkers (pTau181, pTau231, pTau217) are significantly elevated in Aβ-positive individuals, with stronger Aβ–pTau associations observed in APOE ε4 carriers (CPAS: β = 0.26, p = 0.003 for pTau231; ADNI: β = 0.45, p < 0.001 for pTau181). Across two cohorts, plasma GFAP levels significantly strengthened the associations between pTau biomarkers and Tau PET. Furthermore, subsequent analyses revealed that this modulatory effect of GFAP on the links between pTau and PET-derived pathological changes was more pronounced in APOE ε4 non-carriers, whereas in APOE ε4 carriers, a significant interaction between GFAP and pTau was only observed in specific Braak stage-specific regions within the CPAS cohort. In longitudinal analyses, we also observed stronger pTau181-associated longitudinal tau accumulation in individuals with high GFAP levels (Braak III-IV). We demonstrate that APOE ε4 status critically modulates the relationship between pTau and Aβ pathology, whereas plasma GFAP primarily influences pTau–tau pathology associations, particularly in individuals without APOE ε4 allele. These findings underscore the role of reactive astrogliosis in tau propagation and support the utility of plasma biomarkers for AD diagnosis and prognosis.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"85 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145397986","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":"Microglia sensing of peripheral signals that bridge the brain and body","authors":"Claire E. Young, Melanie A. Samuel","doi":"10.1186/s13024-025-00905-1","DOIUrl":"https://doi.org/10.1186/s13024-025-00905-1","url":null,"abstract":"Microglia are the resident immune cell of the brain, and alterations in microglia signaling have been implicated in many neurodegenerative disorders. While microglia responses to central cues and other brain cell types are well documented, studies are increasingly investigating the impact of peripherally derived signals on microglia function. A diverse array of peripheral cues, including dietary components, hormones, and bacteria metabolites and components from the microbiome cross the blood brain barrier and directly influence microglia state through ligand-receptor interactions. This review highlights the complexity of brain-body interactions from the perspective of microglia function and proposes the idea that microglia could serve as a central hub of detection and regulation of body state changes. In addition, improving understanding of how microglia respond to peripheral cues will allow for improved preclinical experimental design. As peripheral cues have the potential to be more readily manipulated than central cues, these interactions also have implications for the treatment of many diseases and neurodegenerative disorders. ","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"36 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145397987","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}