Molecular Neurodegeneration最新文献

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

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

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

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

{"title":"A reciprocal relationship between markers of genomic DNA damage and alpha-synuclein pathology in dementia with Lewy bodies","authors":"David J. Koss, Olivia Todd, Hariharan Menon, Zoe Anderson, Tamsin Yang, Lucas Findlay, Ben Graham, Pawel Palmowski, Andrew Porter, Nicola Morrice, Lauren Walker, Johannes Attems, Simona S. Ghanem, Omar El-Agnaf, Fiona EN. LeBeau, Daniel Erskine, Tiago F. Outeiro","doi":"10.1186/s13024-025-00813-4","DOIUrl":"https://doi.org/10.1186/s13024-025-00813-4","url":null,"abstract":"DNA damage and DNA damage repair (DDR) dysfunction are insults with broad implications for cellular physiology and have been implicated in various neurodegenerative diseases. Alpha-synuclein (aSyn), a pre-synaptic and nuclear protein associated with neurodegenerative disorders known as synucleinopathies, has been associated with DNA double strand break (DSB) repair. However, although nuclear aSyn pathology has been observed in cortical tissue of dementia with Lewy body (DLB) cases, whether such nuclear pathology coincides with the occurrence of DNA damage has not previously been investigated. Moreover, the specific types of DNA damage elevated in DLB cases and the contribution of DNA damage towards Lewy body (LB) formation is unknown. DNA damage and aSyn pathology were assessed in fixed lateral temporal cortex from clinically and neuropathologically confirmed DLB cases and controls, as well as in cortical tissue from young 3-month-old presymptomatic A30P-aSyn mice. Frozen lateral temporal cortex from DLB and control cases was subject to nuclear isolation, western blotting, aSyn seed amplification and proteomic characterisation via mass spectrometry. We detected seed-competent nuclear aSyn, and elevated nuclear serine-129 phosphorylation in DLB temporal cortex, alongside the accumulation of DSBs in neuronal and non-neuronal cellular populations. DNA damage was also present in cortical tissue from presymptomatic A30P mice, demonstrating it is an early insult closely associated with pathogenic aSyn. Strikingly, in postmortem DLB tissue, markers of genomic DNA damage-derived cytoplasmic DNA (CytoDNA) were evident within the majority of LBs examined. The observed cellular pathology was consistent with nuclear upregulation of associated DDR proteins, particularly those involved in base excision repair and DSB repair pathways. Collectively our study demonstrates the accumulation of seed-competent pathological nuclear associated aSyn, alongside nuclear DNA damage and the potential involvement of DNA damage derived cytoDNA species in cytoplasmic aSyn pathology. Ultimately, our study supports the hypothesis of a reciprocal relationship between aSyn pathology and nuclear DNA damage and highlights a potential underlying role for DNA damage in pathological mechanisms relevant to DLB, as well as other synucleinopathies, opening novel possibilities for diagnosis and treatment.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"56 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143666069","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":"Alpha synuclein co-pathology is associated with accelerated amyloid-driven tau accumulation in Alzheimer’s disease","authors":"Nicolai Franzmeier, Sebastian Niclas Roemer-Cassiano, Alexander Maximilian Bernhardt, Amir Dehsarvi, Anna Dewenter, Anna Steward, Davina Biel, Lukas Frontzkowski, Zeyu Zhu, Johannes Gnörich, Julia Pescoller, Fabian Wagner, Fabian Hirsch, Hannah de Bruin, Rik Ossenkoppele, Carla Palleis, Felix Strübing, Michael Schöll, Johannes Levin, Matthias Brendel, Günter U. Höglinger","doi":"10.1186/s13024-025-00822-3","DOIUrl":"https://doi.org/10.1186/s13024-025-00822-3","url":null,"abstract":"Aggregated alpha-Synuclein (αSyn) is a hallmark pathology in Parkinson’s disease but also one of the most common co-pathologies in Alzheimer’s disease (AD). Preclinical studies suggest that αSyn can exacerbate tau aggregation, implying that αSyn co-pathology may specifically contribute to the Aβ-induced aggregation of tau that drives neurodegeneration and cognitive decline in AD. To investigate this, we combined a novel CSF-based seed-amplification assay (SAA) to determine αSyn positivity with amyloid- and tau-PET neuroimaging in a large cohort ranging from cognitively normal individuals to those with dementia, examining whether αSyn co-pathology accelerates Aβ-driven tau accumulation and cognitive decline. In 284 Aβ-positive and 308 Aβ-negative subjects, we employed amyloid-PET, Flortaucipir tau-PET, and a CSF-based αSyn seed-amplification assay (SAA) to detect in vivo αSyn aggregation. CSF p-tau181 measures were available for 384 subjects to assess earliest tau abnormalities. A subset of 155 Aβ-positive and 135 Aβ-negative subjects underwent longitudinal tau-PET over approximately 2.5 years. Using linear regression models, we analyzed whether αSyn SAA positivity was linked to stronger Aβ-related increases in baseline fluid and PET tau biomarkers, faster Aβ-driven tau-PET increase, and more rapid cognitive decline. αSyn SAA positivity was more common in Aβ + vs. Aβ- subjects and increased with clinical severity (p < 0.001). Most importantly, αSyn positivity was also associated with greater amyloid-associated CSF p-tau181 increases (p = 0.005) and higher tau-PET levels in AD-typical brain regions (p = 0.006). Longitudinal analyses confirmed further that αSyn positivity was associated with faster amyloid-related tau accumulation (p = 0.029) and accelerated amyloid-related cognitive decline, potentially driven driven by stronger tau pathology. Our findings suggest that αSyn co-pathology, detectable via CSF-based SAAs, is more prevalent in advanced AD and contributes to the development of aggregated tau pathology thereby driving faster cognitive decline. This highlights that a-Syn co-pathology may specifically accelerate amyloid-driven tau pathophysiology in AD, underscoring the need to consider αSyn in AD research and treatment strategies.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"43 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143640651","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":"Alzheimer's disease neuropathology and its estimation with fluid and imaging biomarkers","authors":"Dietmar Rudolf Thal, Koen Poesen, Rik Vandenberghe, Steffi De Meyer","doi":"10.1186/s13024-025-00819-y","DOIUrl":"https://doi.org/10.1186/s13024-025-00819-y","url":null,"abstract":"Alzheimer’s disease (AD) is neuropathologically characterized by the extracellular deposition of the amyloid-β peptide (Aβ) and the intraneuronal accumulation of abnormal phosphorylated tau (τ)-protein (p-τ). Most frequently, these hallmark lesions are accompanied by other co-pathologies in the brain that may contribute to cognitive impairment, such as vascular lesions, intraneuronal accumulation of phosphorylated transactive-response DNA-binding protein 43 (TDP-43), and/or α-synuclein (αSyn) aggregates. To estimate the extent of these AD and co-pathologies in patients, several biomarkers have been developed. Specific tracers target and visualize Aβ plaques, p-τ and αSyn pathology or inflammation by positron emission tomography. In addition to these imaging biomarkers, cerebrospinal fluid, and blood-based biomarker assays reflecting AD-specific or non-specific processes are either already in clinical use or in development. In this review, we will introduce the pathological lesions of the AD brain, the related biomarkers, and discuss to what extent the respective biomarkers estimate the pathology determined at post-mortem histopathological analysis. It became evident that initial stages of Aβ plaque and p-τ pathology are not detected with the currently available biomarkers. Interestingly, p-τ pathology precedes Aβ deposition, especially in the beginning of the disease when biomarkers are unable to detect it. Later, Aβ takes the lead and accelerates p-τ pathology, fitting well with the known evolution of biomarker measures over time. Some co-pathologies still lack clinically established biomarkers today, such as TDP-43 pathology or cortical microinfarcts. In summary, specific biomarkers for AD-related pathologies allow accurate clinical diagnosis of AD based on pathobiological parameters. Although current biomarkers are excellent measures for the respective pathologies, they fail to detect initial stages of the disease for which post-mortem analysis of the brain is still required. Accordingly, neuropathological studies remain essential to understand disease development especially in early stages. Moreover, there is an urgent need for biomarkers reflecting co-pathologies, such as limbic predominant, age-related TDP-43 encephalopathy-related pathology, which is known to modify the disease by interacting with p-τ. Novel biomarker approaches such as extracellular vesicle-based assays and cryptic RNA/peptides may help to better detect these co-pathologies in the future.\u0000","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"26 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143618413","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":"Probe-dependent Proximity Profiling (ProPPr) Uncovers Similarities and Differences in Phospho-Tau-Associated Proteomes Between Tauopathies","authors":"Dmytro Morderer, Melissa C. Wren, Feilin Liu, Naomi Kouri, Anastasiia Maistrenko, Bilal Khalil, Nora Pobitzer, Michelle R. Salemi, Brett S. Phinney, Guojun Bu, Na Zhao, Dennis W. Dickson, Melissa E. Murray, Wilfried Rossoll","doi":"10.1186/s13024-025-00817-0","DOIUrl":"https://doi.org/10.1186/s13024-025-00817-0","url":null,"abstract":"Tauopathies represent a diverse group of neurodegenerative disorders characterized by the abnormal aggregation of the microtubule-associated protein tau. Despite extensive research, the mechanisms underlying the diversity of neuronal and glial tau pathology in different tauopathies are poorly understood. While there is a growing understanding of tauopathy-specific differences in tau isoforms and fibrillar structures, the specific composition of heterogenous tau lesions remains unknown. Here we study the protein composition of tau aggregates in four major tauopathies: Alzheimer's disease (AD), corticobasal degeneration (CBD), Pick's disease (PiD), and progressive supranuclear palsy (PSP). We developed an approach for in situ proximity labeling and isolation of aggregate-associated proteins using glass slides with formalin-fixed paraffin-embedded (FFPE) human postmortem brain tissue, termed Probe-dependent Proximity Profiling (ProPPr). We used ProPPr for the analysis of proteomes associated with AT8-positive cellular lesions from frontal cortices. Isolated proximity proteomes were analyzed by data-independent acquisition mass spectrometry. Co-immunofluorescence staining and quantitative data analysis for selected proteins in human brain tissue was performed to further investigate associations with diverse tau pathologies. Proteomics data analysis identified numerous common and tauopathy-specific proteins associated with phospho-tau aggregates. Extensive validations of candidates through quantitative immunofluorescence imaging of distinct aggregates across disease cases demonstrate successful implementation of ProPPr for unbiased discovery of aggregate-associated proteins in in human brain tissue. Our results reveal the association of retromer complex component vacuolar protein sorting-associated protein 35 (VPS35) and lysosome-associated membrane glycoprotein 2 (LAMP2) with specific types of phospho-tau lesions in tauopathies. Furthermore, we discovered a disease-specific association of certain proteins with distinct pathological lesions, including glycogen synthase kinase alpha (GSK3α), ferritin light chain (FTL), and the neuropeptide precursor VGF. Notably, the identification of FTL-positive microglia in CBD astrocytic plaques indicate their potential role in the pathogenesis of these lesions. Our findings demonstrate the suitability of the ProPPr approach in FFPE brain tissue for unbiased discovery of local proteomes that provide valuable insights into the underlying proteomic landscape of tauopathies, shedding light on the molecular mechanisms underlying tau pathology. This first comprehensive characterization of tau-associated proteomes in a range of distinct tauopathies enhances our understanding of disease heterogeneity and mechanisms, informing strategies for the development of diagnostic biomarkers and targeted therapies.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"113 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143608076","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":"Comprehensive cross-sectional and longitudinal comparisons of plasma glial fibrillary acidic protein and neurofilament light across FTD spectrum disorders","authors":"Udit Sheth, Linn Öijerstedt, Michael G. Heckman, Launia J. White, Hilary W. Heuer, Argentina Lario Lago, Leah K. Forsberg, Kelley M. Faber, Tatiana M. Foroud, Rosa Rademakers, Eliana Marisa Ramos, Brian S. Appleby, Andrea C. Bozoki, R. Ryan Darby, Bradford C. Dickerson, Kimiko Domoto-Reilly, Douglas R. Galasko, Nupur Ghoshal, Neill R. Graff-Radford, Ian M. Grant, Chadwick M. Hales, Ging-Yuek Robin Hsiung, Edward D. Huey, David Irwin, Justin Y. Kwan, Irene Litvan, Ian R. Mackenzie, Joseph C. Masdeu, Mario F. Mendez, Chiadi U. Onyike, Belen Pascual, Peter S. Pressman, Erik D. Roberson, Allison Snyder, M. Carmela Tartaglia, William W. Seeley, Dennis W. Dickson, Howard J. Rosen, Bradley F. Boeve, Adam L. Boxer, Leonard Petrucelli, Tania F. Gendron","doi":"10.1186/s13024-025-00821-4","DOIUrl":"https://doi.org/10.1186/s13024-025-00821-4","url":null,"abstract":"Therapeutic development for frontotemporal dementia (FTD) is hindered by the lack of biomarkers that inform susceptibility/risk, prognosis, and the underlying causative pathology. Blood glial fibrillary acidic protein (GFAP) has garnered attention as a FTD biomarker. However, investigations of GFAP in FTD have been hampered by symptomatic and histopathologic heterogeneity and small cohort sizes contributing to inconsistent findings. Therefore, we evaluated plasma GFAP as a FTD biomarker and compared its performance to that of neurofilament light (NfL) protein, a leading FTD biomarker. We availed ARTFL LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) study resources to conduct a comprehensive cross-sectional and longitudinal examination of the susceptibility/risk, prognostic, and predictive performance of GFAP and NfL in the largest series of well-characterized presymptomatic FTD mutation carriers and participants with sporadic or familial FTD syndromes. Utilizing single molecule array technology, we measured GFAP and NfL in plasma from 161 controls, 127 presymptomatic mutation carriers, 702 participants with a FTD syndrome, and 67 participants with mild behavioral and/or cognitive changes. We used multivariable linear regression and Cox proportional hazard models adjusted for co-variates to examine the biomarker utility of baseline GFAP and NfL concentrations or their rates of change. Compared to controls, GFAP and NfL were elevated in each FTD syndrome but GFAP, unlike NfL, poorly discriminated controls from participants with mild symptoms. Similarly, both baseline GFAP and NfL were higher in presymptomatic mutation carriers who later phenoconverted, but NfL better distinguished non-converters from phenoconverters. We additionally observed that GFAP and NfL were associated with disease severity indicators and survival, but NfL far outperformed GFAP. Nevertheless, we validated findings that the GFAP/NfL ratio may discriminate frontotemporal lobar degeneration with tau versus TDP-43 pathology. Our head-to-head comparison of plasma GFAP and NfL as biomarkers for FTD indicate that NfL consistently outmatched GFAP as a prognostic and predictive biomarker for participants with a FTD syndrome, and as a susceptibility/risk biomarker for people at genetic risk of FTD. Our findings underscore the need to include leading biomarkers in investigations evaluating new biomarkers if the field is to fully ascertain their performance and clinical value.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"26 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143608080","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A versatile mouse model to advance human microglia transplantation research in neurodegenerative diseases","authors":"Lutgarde Serneels, Annerieke Sierksma, Emanuela Pasciuto, Ivana Geric, Arya Nair, Anna Martinez-Muriana, An Snellinx, Bart De Strooper","doi":"10.1186/s13024-025-00823-2","DOIUrl":"https://doi.org/10.1186/s13024-025-00823-2","url":null,"abstract":"Recent studies highlight the critical role of microglia in neurodegenerative disorders, and emphasize the need for humanized models to accurately study microglial responses. Human-mouse microglia xenotransplantation models are a valuable platform for functional studies and for testing therapeutic approaches, yet currently those models are only available for academic research. This hampers their implementation for the development and testing of medication that targets human microglia. We developed the hCSF1Bdes mouse line, which is suitable as a new transplantation model and available to be crossed to any disease model of interest. The hCSF1Bdes model created by CRISPR gene editing is RAG2 deficient and expresses human CSF1. Additionally, we crossed this model with two humanized App KI mice, the AppHu and the AppSAA. Flow cytometry, immunohistochemistry and bulk sequencing was used to study the response of microglia in the context of Alzheimer’s disease. Our results demonstrate the successful transplantation of iPSC-derived human microglia into the brains of hCSF1Bdes mice without triggering a NK-driven immune response. Furthermore, we confirmed the multipronged response of microglia in the context of Alzheimer’s disease. The hCSF1Bdes and the crosses with the Alzheimer’s disease knock-in model AppSAA and the humanized App knock-in control mice, AppHu are deposited with EMMA and fully accessible to the research community. The hCSF1Bdes mouse is available for both non-profit and for-profit organisations, facilitating the use of the xenotransplantation paradigm for human microglia to study complex human disease.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"37 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143589764","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}