Pub Date : 2025-10-29DOI: 10.1186/s13024-025-00905-1
Claire E. Young, Melanie A. Samuel
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.
{"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}
The potential neuroprotective effects of antidiabetic treatments have been largely assessed in Alzheimer's disease (AD) and AD-like dementia models, with or without metabolic disorders. In this Line, these effects Have also been addressed in wide population-based studies or in patients with mild cognitive impairment, AD, diabetes or combined pathologies. Most common treatments include glucagon-like peptide 1 receptor agonists; thiazolidinediones; biguanides; sulphonylureas; dipeptidyl peptidase-4 inhibitors, insulin, amylin and others. To assess their impact, we have conducted a systematic search in PubMed to Identify studies addressing the effect of Antidiabetic treatments on AD or AD-like dementia preclinical models And clinical studies, yielding 3560 research items. After screening titles And abstracts, 380 papers met eligibility criteria (original full-text articles, written in English, focused on AD or AD-like dementia, involving antidiabetic treatments, containing data on neuropathological AD markers and/or cognitive function, and conducted in vivo or ex vivo), And 25 additional papers were added through citations, resulting in a Total of 405 primary research articles published between 1996 And 2024. We have reviewed the effects of antidiabetic treatments on tau pathology, neuronal health, oxidative stress and neuroinflammation, vascular alterations, implicated signaling pathways and cognitive function in AD and AD-like dementia preclinical models and patients. Overall, antidiabetic medications represent a promising therapeutic strategy to tackle neurodegeneration and cognitive decline in AD preclinical models. Nevertheless, further research is needed to optimize their clinical effectiveness.
{"title":"Effect of antidiabetic drugs in Alzheimer´s disease: a systematic review of preclinical and clinical studies.","authors":"Miriam Corraliza-Gomez,Maria Vargas-Soria,Monica Garcia-Alloza","doi":"10.1186/s13024-025-00894-1","DOIUrl":"https://doi.org/10.1186/s13024-025-00894-1","url":null,"abstract":"The potential neuroprotective effects of antidiabetic treatments have been largely assessed in Alzheimer's disease (AD) and AD-like dementia models, with or without metabolic disorders. In this Line, these effects Have also been addressed in wide population-based studies or in patients with mild cognitive impairment, AD, diabetes or combined pathologies. Most common treatments include glucagon-like peptide 1 receptor agonists; thiazolidinediones; biguanides; sulphonylureas; dipeptidyl peptidase-4 inhibitors, insulin, amylin and others. To assess their impact, we have conducted a systematic search in PubMed to Identify studies addressing the effect of Antidiabetic treatments on AD or AD-like dementia preclinical models And clinical studies, yielding 3560 research items. After screening titles And abstracts, 380 papers met eligibility criteria (original full-text articles, written in English, focused on AD or AD-like dementia, involving antidiabetic treatments, containing data on neuropathological AD markers and/or cognitive function, and conducted in vivo or ex vivo), And 25 additional papers were added through citations, resulting in a Total of 405 primary research articles published between 1996 And 2024. We have reviewed the effects of antidiabetic treatments on tau pathology, neuronal health, oxidative stress and neuroinflammation, vascular alterations, implicated signaling pathways and cognitive function in AD and AD-like dementia preclinical models and patients. Overall, antidiabetic medications represent a promising therapeutic strategy to tackle neurodegeneration and cognitive decline in AD preclinical models. Nevertheless, further research is needed to optimize their clinical effectiveness.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"39 1","pages":"112"},"PeriodicalIF":15.1,"publicationDate":"2025-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145374048","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}
BACKGROUNDThe accumulation and propagation of α-synuclein (α-syn) are hallmark features of Parkinson's disease (PD) and related neurodegenerative disorders. O-GlcNAcylation, an abundant post-translational modification throughout the brain, is regulated by the enzymatic activity of the cycling enzymes O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) and has been implicated in altering α-syn toxicity. Nevertheless, the interplay between modulating O-GlcNAc cycling and α-syn aggregation and the propagation of amyloid pathology is not well elucidated.METHODSTo this end, we delivered conformational strains of α-syn in the striatum of mice or neuronal and microglial co-cultured cells following pharmacologically or genetically inhibited OGT and OGA. The substantia nigra was injected with an adeno-associated viral vector coding for α-syn combined with α-syn preformed fibrils to examine α-syn-induced dopaminergic cytotoxicity. The α-syn pathology and spreading, protein O-GlcNAcylation, OGT and OGA levels, microglial inflammation, and behavioral impairments were evaluated. Furthermore, the O-GlcNAc modification and proteolysis status of α-syn under O-GlcNAc cycling modification were also assessed using a combination of approaches, including Click-iT™ O-GlcNAc enzyme labeling, sWGA pulldown, HPLC-MS/MS, and immunohistochemical analysis following proteasome and autophagy-lysosome inhibition.RESULTSWe found that modulation of O-GlcNAc cycling, governed by the two enzymes OGT and OGA, significantly affected α-syn aggregation, propagation, dopaminergic neuronal degeneration, and microglial inflammation. Pathological α-syn transmission to adjacent cells and anatomically connected brain regions was found to suppress recipient cellular O-GlcNAc levels, concomitant with reduced OGT expression. Pharmacological inhibition or genetic knockdown of OGT exacerbated α-syn aggregation, enhanced its intercellular transmission, and intensified NOD-, LRR-, and pyrin domain-containing 3 (NLRP3)-mediated microglial inflammation. Conversely, increasing O-GlcNAcylation via OGA inhibition ameliorated these pathological processes. Furthermore, we demonstrate that enzymatic O-GlcNAcylation significantly regulates the aggregation of fibril-induced initial dimer formation and facilitates the clearance of α-syn aggregates through autophagosome-lysosome flux.CONCLUSIONSThese findings highlight the critical regulatory role of O-GlcNAc modification in α-syn pathology and conformational strain formation, and provide mechanical evidence that enhancing O-GlcNAc modifications alleviates pathological α-syn proteolysis by restoring autophagosome-lysosome flux.
{"title":"Modulation of O-GlcNAc cycling influences α-synuclein amplification, degradation, and associated neuroinflammatory pathology.","authors":"Yongzhen Miao,Ting Zhang,Zhuoya Ma,Huanhuan Du,Qipei Gu,Mengni Jiang,Kangping Xiong,Chun-Feng Liu,Hongrui Meng","doi":"10.1186/s13024-025-00904-2","DOIUrl":"https://doi.org/10.1186/s13024-025-00904-2","url":null,"abstract":"BACKGROUNDThe accumulation and propagation of α-synuclein (α-syn) are hallmark features of Parkinson's disease (PD) and related neurodegenerative disorders. O-GlcNAcylation, an abundant post-translational modification throughout the brain, is regulated by the enzymatic activity of the cycling enzymes O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) and has been implicated in altering α-syn toxicity. Nevertheless, the interplay between modulating O-GlcNAc cycling and α-syn aggregation and the propagation of amyloid pathology is not well elucidated.METHODSTo this end, we delivered conformational strains of α-syn in the striatum of mice or neuronal and microglial co-cultured cells following pharmacologically or genetically inhibited OGT and OGA. The substantia nigra was injected with an adeno-associated viral vector coding for α-syn combined with α-syn preformed fibrils to examine α-syn-induced dopaminergic cytotoxicity. The α-syn pathology and spreading, protein O-GlcNAcylation, OGT and OGA levels, microglial inflammation, and behavioral impairments were evaluated. Furthermore, the O-GlcNAc modification and proteolysis status of α-syn under O-GlcNAc cycling modification were also assessed using a combination of approaches, including Click-iT™ O-GlcNAc enzyme labeling, sWGA pulldown, HPLC-MS/MS, and immunohistochemical analysis following proteasome and autophagy-lysosome inhibition.RESULTSWe found that modulation of O-GlcNAc cycling, governed by the two enzymes OGT and OGA, significantly affected α-syn aggregation, propagation, dopaminergic neuronal degeneration, and microglial inflammation. Pathological α-syn transmission to adjacent cells and anatomically connected brain regions was found to suppress recipient cellular O-GlcNAc levels, concomitant with reduced OGT expression. Pharmacological inhibition or genetic knockdown of OGT exacerbated α-syn aggregation, enhanced its intercellular transmission, and intensified NOD-, LRR-, and pyrin domain-containing 3 (NLRP3)-mediated microglial inflammation. Conversely, increasing O-GlcNAcylation via OGA inhibition ameliorated these pathological processes. Furthermore, we demonstrate that enzymatic O-GlcNAcylation significantly regulates the aggregation of fibril-induced initial dimer formation and facilitates the clearance of α-syn aggregates through autophagosome-lysosome flux.CONCLUSIONSThese findings highlight the critical regulatory role of O-GlcNAc modification in α-syn pathology and conformational strain formation, and provide mechanical evidence that enhancing O-GlcNAc modifications alleviates pathological α-syn proteolysis by restoring autophagosome-lysosome flux.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"13 1","pages":"113"},"PeriodicalIF":15.1,"publicationDate":"2025-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145374047","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 : 2025-10-23DOI: 10.1186/s13024-025-00890-5
Frances Theunissen,Loren Flynn,Alfredo Iacoangeli,Ahmad Al Khleifat,Ammar Al-Chalabi,James J Giordano,Masha Strømme,P Anthony Akkari
With the disease modifying therapy Qalsody (tofersen) which targets the RNA product of the SOD1 gene, having been shown effective in amyotrophic lateral sclerosis (ALS), the present perspective seeks to explore progress towards the implementation of precision medicine principles in ALS drug development. We address the advances in our understanding of the complex genetic architecture of ALS, including the varying models of genetic contribution to disease, and the importance of understanding population genetics and genetic testing when considering patient selection for clinical studies. Additionally, we discuss the advances in long-read whole-genome sequencing technology and how this method can improve streamlined genetic testing and our understanding of the genetic heterogeneity in ALS. We highlight the recent advances in omics-data for understanding ALS patient sub-groups and how this knowledge should be applied to pre-clinical drug development in a proposed patient profiling workflow, particularly for gene targeted therapies. Finally, we summarise key ethical considerations that are pertinent to equitable care for patients, as we enter the era of precision medicine to treat ALS.
{"title":"Entering the era of precision medicine to treat amyotrophic lateral sclerosis.","authors":"Frances Theunissen,Loren Flynn,Alfredo Iacoangeli,Ahmad Al Khleifat,Ammar Al-Chalabi,James J Giordano,Masha Strømme,P Anthony Akkari","doi":"10.1186/s13024-025-00890-5","DOIUrl":"https://doi.org/10.1186/s13024-025-00890-5","url":null,"abstract":"With the disease modifying therapy Qalsody (tofersen) which targets the RNA product of the SOD1 gene, having been shown effective in amyotrophic lateral sclerosis (ALS), the present perspective seeks to explore progress towards the implementation of precision medicine principles in ALS drug development. We address the advances in our understanding of the complex genetic architecture of ALS, including the varying models of genetic contribution to disease, and the importance of understanding population genetics and genetic testing when considering patient selection for clinical studies. Additionally, we discuss the advances in long-read whole-genome sequencing technology and how this method can improve streamlined genetic testing and our understanding of the genetic heterogeneity in ALS. We highlight the recent advances in omics-data for understanding ALS patient sub-groups and how this knowledge should be applied to pre-clinical drug development in a proposed patient profiling workflow, particularly for gene targeted therapies. Finally, we summarise key ethical considerations that are pertinent to equitable care for patients, as we enter the era of precision medicine to treat ALS.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"39 1","pages":"111"},"PeriodicalIF":15.1,"publicationDate":"2025-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145351490","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 : 2025-10-17DOI: 10.1186/s13024-025-00896-z
Heeyoung An, Sora Kang, Jaejin Shin, Purum Kim, Sunpil Kim, Suyeol Im, Ji Hwan Kim, Keun Woo Lee, Dong Hwan Kim, Jung Hee Park, Min-Ho Park, Jaemin Lee, Sun Kyung Park, Kwang Pyo Kim, Hyeong Min Lee, Jae Ho Lee, Leo S. Choi, Hyun Ju Jeon, Suyeon Yellena Kim, In Young Hwang, Mridula Bhalla, Woojin Won, Hyung Soon Park, Sang-Ku Yoo, Byoung Dae Lee, C. Justin Lee, Youngmi Kim Pak
Parkinson’s disease (PD) is the second most prevalent neurodegenerative disease characterized by motor impairment resulting from the degeneration of dopaminergic neurons in the substantia nigra, alongside α -synuclein (α-syn) accumulation, mitochondrial dysfunction, and oxidative stress. Recent studies on PD treatment have focused primarily on exploring oxidative stress and mitochondrial function as ways to restore dopamine release. Notably, previous studies have demonstrated that Paraoxonase 2 (PON2) plays a critical role in neuroprotection and neuroinflammation by reducing oxidative stress in striatal neurons and astrocytes. In this study, we investigated the potential therapeutic effect of a newly developed drug, Vutiglabridin, which is demonstrated to augment the activity of PON2 in the mouse model of PD. We assessed the impact of Vutiglabridin in a PD model induced by MPP+ treatment and overexpression of the A53T mutated α-syn. Furthermore, we administered Vutiglabridin subsequent to PON2 gene knockdown through PON2-shRNA overexpression to elucidate the interplay between PON2 and Vutiglabridin. Vutiglabridin effectively crosses the blood-brain barrier (BBB) and maintains a presence in the brain for over 24 h, achieving concentrations up to 2.5 times higher than in the bloodstream. It successfully binds to PON2 in both its (R) and (S) forms. Vutiglabridin reversed mitochondrial dysfunction, reduced oxidative stress, improved motor functions, and protected dopaminergic neurons against MPP+-induced damage. Similarly, in α-syn A53T overexpressed PD models, it not only reduced astrocytic reactivity and microglia activation but also doubled the tyrosine hydroxylase positive neurons /dopa decarboxylase positive neurons (TH+/DDC+) ratio, signifying enhanced neuronal health. However, these positive outcomes were absent in PON2-knockdown mice, underscoring Vutiglabridin’s reliance on PON2 for its neuroprotective effects. These findings indicate that Vutiglabridin may serve as a promising therapeutic approach for reducing reactive oxygen species (ROS) levels by modulating PON2 activity in Parkinson’s diseases.
{"title":"Neurotherapeutic effects of Vutiglabridin as a Paraoxonase-2 modulator in preclinical models of Parkinson’s disease","authors":"Heeyoung An, Sora Kang, Jaejin Shin, Purum Kim, Sunpil Kim, Suyeol Im, Ji Hwan Kim, Keun Woo Lee, Dong Hwan Kim, Jung Hee Park, Min-Ho Park, Jaemin Lee, Sun Kyung Park, Kwang Pyo Kim, Hyeong Min Lee, Jae Ho Lee, Leo S. Choi, Hyun Ju Jeon, Suyeon Yellena Kim, In Young Hwang, Mridula Bhalla, Woojin Won, Hyung Soon Park, Sang-Ku Yoo, Byoung Dae Lee, C. Justin Lee, Youngmi Kim Pak","doi":"10.1186/s13024-025-00896-z","DOIUrl":"https://doi.org/10.1186/s13024-025-00896-z","url":null,"abstract":"Parkinson’s disease (PD) is the second most prevalent neurodegenerative disease characterized by motor impairment resulting from the degeneration of dopaminergic neurons in the substantia nigra, alongside α -synuclein (α-syn) accumulation, mitochondrial dysfunction, and oxidative stress. Recent studies on PD treatment have focused primarily on exploring oxidative stress and mitochondrial function as ways to restore dopamine release. Notably, previous studies have demonstrated that Paraoxonase 2 (PON2) plays a critical role in neuroprotection and neuroinflammation by reducing oxidative stress in striatal neurons and astrocytes. In this study, we investigated the potential therapeutic effect of a newly developed drug, Vutiglabridin, which is demonstrated to augment the activity of PON2 in the mouse model of PD. We assessed the impact of Vutiglabridin in a PD model induced by MPP+ treatment and overexpression of the A53T mutated α-syn. Furthermore, we administered Vutiglabridin subsequent to PON2 gene knockdown through PON2-shRNA overexpression to elucidate the interplay between PON2 and Vutiglabridin. Vutiglabridin effectively crosses the blood-brain barrier (BBB) and maintains a presence in the brain for over 24 h, achieving concentrations up to 2.5 times higher than in the bloodstream. It successfully binds to PON2 in both its (R) and (S) forms. Vutiglabridin reversed mitochondrial dysfunction, reduced oxidative stress, improved motor functions, and protected dopaminergic neurons against MPP+-induced damage. Similarly, in α-syn A53T overexpressed PD models, it not only reduced astrocytic reactivity and microglia activation but also doubled the tyrosine hydroxylase positive neurons /dopa decarboxylase positive neurons (TH+/DDC+) ratio, signifying enhanced neuronal health. However, these positive outcomes were absent in PON2-knockdown mice, underscoring Vutiglabridin’s reliance on PON2 for its neuroprotective effects. These findings indicate that Vutiglabridin may serve as a promising therapeutic approach for reducing reactive oxygen species (ROS) levels by modulating PON2 activity in Parkinson’s diseases.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"12 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145311257","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 : 2025-10-17DOI: 10.1186/s13024-025-00901-5
Mariana I Muñoz-García,Yuetiva Deming,Ferran Lugo-Hernández,Sterling Johnson,Sanjay Asthana,Gwendlyn Kollmorgen,Clara Quijano-Rubio,Cynthia Carlsson,Ozioma C Okonkwo,David Pérez-Martinez,Alberto Villarejo-Galende,Kaj Blennow,Marc Suárez-Calvet,Henrik Zetterberg,Barbara B Bendlin,Estrella Morenas-Rodríguez
BACKGROUNDSynaptic homeostasis, maintained by microglia and astroglia, is disrupted throughout aging and early on in neurodegenerative diseases. Our aim was to study the relationship between TREM2-dependent microglial reactivity, astroglial response and synaptic dysfunction in two longitudinal cohorts of cognitively healthy volunteers and determine whether this relationship is influenced by AD core biomarkers.METHODSWe analyzed cross-sectional and longitudinal associations between cerebrospinal fluid levels of soluble TREM2 (sTREM2), astroglial markers (GFAP, S100B), and synaptic markers (neurogranin, α-synuclein) in cognitively unimpaired participants from the Wisconsin Registry for Alzheimer's Prevention (WRAP) and the Alzheimer's and Families (ALFA+) cohort. Biomarkers were quantified using validated immunoassays (NeuroToolKit, Roche), with sTREM2 measured using an in-house MSD-based assay in the WRAP cohort. Linear regression and linear mixed-effects models were used, both unadjusted and adjusted for Aβ42 and p-tau. Subgroup analyses were performed based on AT classification, APOE-ε4 status, and median splits of Aβ42/Aβ40 ratio and p-tau, to capture profiles suggestive of early AD-related neuropathogenesis.RESULTSWe found significant cross-sectional associations between sTREM2 and α-synuclein, as well as between sTREM2 and S100B, in subgroups exhibiting AD-related biomarker profiles. Longitudinally, lower baseline neurogranin and α-synuclein and higher S100B predicted greater increases in sTREM2 over time independently of AD-related markers in the WRAP cohort (β = -0.02, p = 0.006; β = -0.02, p = 0.01; β = 0.02, p = 0.03, respectively). In ALFA+, lower baseline α-synuclein also predicted a greater subsequent longitudinal increase in sTREM2, but only among individuals with Aβ42/Aβ40 ratio above the median (β = -0.01, p = 0.05). Notably, higher baseline sTREM2 was associated with a smaller longitudinal increase in neurogranin in both cohorts (β = -0.01, p = 0.03 for WRAP, β = -0.01, p = 0.04 in ALFA+).CONCLUSIONSSynaptic dysfunction markers at baseline influence the longitudinal dynamics of CSF sTREM2 independently of AD-pathology related biomarkers throughout aging and earliest stages of neurodegeneration. In turn, higher baseline sTREM2 is associated with more stable neurogranin levels over time. These results suggest an independent interaction between synaptic dysfunction and TREM2-dependent microglial activation throughout aging and early neurodegeneration beyond AD pathology.
背景：由小胶质细胞和星形胶质细胞维持的突触内稳态在神经退行性疾病的早期和衰老过程中被破坏。我们的目的是研究两个认知健康志愿者纵向队列中trem2依赖性小胶质反应性、星形胶质反应和突触功能障碍之间的关系，并确定这种关系是否受到AD核心生物标志物的影响。方法：我们分析了来自威斯康辛州阿尔茨海默病预防登记中心（WRAP）和阿尔茨海默病及其家族（ALFA+）队列的认知未受损参与者脑脊液中可溶性TREM2 （sTREM2）、星形胶质标志物（GFAP、S100B）和突触标志物（神经颗粒蛋白、α-突触核蛋白）水平的横断和纵向相关性。生物标志物使用经过验证的免疫测定法（NeuroToolKit，罗氏）进行量化，在WRAP队列中使用内部基于msd的测定法测量sTREM2。采用线性回归和线性混合效应模型，对Aβ42和p-tau进行未调整和调整。基于AT分类、APOE-ε4状态、a - β42/ a - β40比值和p-tau的中位数分割进行亚组分析，以获取提示早期ad相关神经发病机制的特征。结果我们发现，在ad相关生物标志物亚组中，sTREM2和α-突触核蛋白之间以及sTREM2和S100B之间存在显著的横断面关联。纵向上，在WRAP队列中，较低的基线神经颗粒蛋白和α-突触核蛋白以及较高的S100B预示着随着时间的推移，与ad相关标志物无关的sTREM2的增加（β = -0.02, p = 0.006; β = -0.02, p = 0.01; β = 0.02, p = 0.03）。在ALFA+中，较低的α-synuclein基线也预示着较高的sTREM2纵向增加，但仅在a - β42/ a - β40比值高于中位数的个体中（β = -0.01, p = 0.05）。值得注意的是，在两个队列中，较高的基线sTREM2与较小的神经颗粒蛋白纵向增加相关（WRAP组β = -0.01, p = 0.03， ALFA+组β = -0.01, p = 0.04）。结论突触功能障碍标志物独立于ad病理相关生物标志物影响脑脊液strem - 2在衰老和神经退行性变早期的纵向动态。反过来，随着时间的推移，较高的基线sTREM2与更稳定的神经颗粒蛋白水平相关。这些结果表明，突触功能障碍和trem2依赖性小胶质细胞激活之间存在独立的相互作用，贯穿衰老和AD病理之外的早期神经退行性变。
{"title":"Synaptic dysfunction and glial activation markers throughout aging and early neurodegeneration: a longitudinal CSF biomarker-based study.","authors":"Mariana I Muñoz-García,Yuetiva Deming,Ferran Lugo-Hernández,Sterling Johnson,Sanjay Asthana,Gwendlyn Kollmorgen,Clara Quijano-Rubio,Cynthia Carlsson,Ozioma C Okonkwo,David Pérez-Martinez,Alberto Villarejo-Galende,Kaj Blennow,Marc Suárez-Calvet,Henrik Zetterberg,Barbara B Bendlin,Estrella Morenas-Rodríguez","doi":"10.1186/s13024-025-00901-5","DOIUrl":"https://doi.org/10.1186/s13024-025-00901-5","url":null,"abstract":"BACKGROUNDSynaptic homeostasis, maintained by microglia and astroglia, is disrupted throughout aging and early on in neurodegenerative diseases. Our aim was to study the relationship between TREM2-dependent microglial reactivity, astroglial response and synaptic dysfunction in two longitudinal cohorts of cognitively healthy volunteers and determine whether this relationship is influenced by AD core biomarkers.METHODSWe analyzed cross-sectional and longitudinal associations between cerebrospinal fluid levels of soluble TREM2 (sTREM2), astroglial markers (GFAP, S100B), and synaptic markers (neurogranin, α-synuclein) in cognitively unimpaired participants from the Wisconsin Registry for Alzheimer's Prevention (WRAP) and the Alzheimer's and Families (ALFA+) cohort. Biomarkers were quantified using validated immunoassays (NeuroToolKit, Roche), with sTREM2 measured using an in-house MSD-based assay in the WRAP cohort. Linear regression and linear mixed-effects models were used, both unadjusted and adjusted for Aβ42 and p-tau. Subgroup analyses were performed based on AT classification, APOE-ε4 status, and median splits of Aβ42/Aβ40 ratio and p-tau, to capture profiles suggestive of early AD-related neuropathogenesis.RESULTSWe found significant cross-sectional associations between sTREM2 and α-synuclein, as well as between sTREM2 and S100B, in subgroups exhibiting AD-related biomarker profiles. Longitudinally, lower baseline neurogranin and α-synuclein and higher S100B predicted greater increases in sTREM2 over time independently of AD-related markers in the WRAP cohort (β = -0.02, p = 0.006; β = -0.02, p = 0.01; β = 0.02, p = 0.03, respectively). In ALFA+, lower baseline α-synuclein also predicted a greater subsequent longitudinal increase in sTREM2, but only among individuals with Aβ42/Aβ40 ratio above the median (β = -0.01, p = 0.05). Notably, higher baseline sTREM2 was associated with a smaller longitudinal increase in neurogranin in both cohorts (β = -0.01, p = 0.03 for WRAP, β = -0.01, p = 0.04 in ALFA+).CONCLUSIONSSynaptic dysfunction markers at baseline influence the longitudinal dynamics of CSF sTREM2 independently of AD-pathology related biomarkers throughout aging and earliest stages of neurodegeneration. In turn, higher baseline sTREM2 is associated with more stable neurogranin levels over time. These results suggest an independent interaction between synaptic dysfunction and TREM2-dependent microglial activation throughout aging and early neurodegeneration beyond AD pathology.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"356 1","pages":"109"},"PeriodicalIF":15.1,"publicationDate":"2025-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145305696","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 : 2025-10-14DOI: 10.1186/s13024-025-00858-5
Emily L. Ward, Larry Benowitz, Thomas M. Brunner, Guojun Bu, Michel Cayouette, Valeria Canto‐Soler, Sandro Dá Mesquita, Adriana Di Polo, Aaron DiAntonio, Xin Duan, Jeffrey L. Goldberg, Zhigang He, Yang Hu, Shane A. Liddelow, Anna La Torre, Milica Margeta, Francisco Quintana, Karthik Shekhar, Beth Stevens, Sally Temple, Humsa Venkatesh, Derek Welsbie, John G. Flanagan
Glaucoma Research Foundation's third Catalyst for a Cure team (CFC3) was established in 2019 to uncover new therapies for glaucoma, a leading cause of blindness. In the 2021 meeting “Solving Neurodegeneration,” (detailed in Mol Neurodegeneration 17(1), 2022) the team examined the failures of investigational monotherapies, issues with translatability, and other significant challenges faced when working with neurodegenerative disease models. They emphasized the need for novel, humanized models and proposed identifying commonalities across neurodegenerative diseases to support the creation of pan-neurodegenerative disease therapies. Since then, the fourth Catalyst for a Cure team (CFC4) was formed to explore commonalities between glaucoma and other neurodegenerative diseases. This review summarizes outcomes from the 2023 “Solving Neurodegeneration 2” meeting, a forum for CFC3 and CFC4 to share updates, problem solve, plan future research collaborations, and identify areas of unmet need or opportunity in glaucoma and the broader field of neurodegenerative disease research. We summarize the recent progress in the field of neurodegenerative disease research and present the newest challenges and opportunities moving forward. While translatability and disease complexity continue to pose major challenges, important progress has been made in identifying neuroprotective targets and understanding neuron-glia-vascular cell interactions. New challenges involve improving our understanding of the disease microenvironment and timeline, identifying the optimal approach(es) to neuronal replacement, and finding the best drug combinations and synergies for neuroprotection. We propose solutions to common research questions, provide prescriptive recommendations for future studies, and detail methodologies, strategies, and approaches for addressing major challenges at the forefront of neurodegenerative disease research. This review is intended to serve as a research framework, offering recommendations and approaches to validating neuroprotective targets, investigating rare cell types, performing cell-specific functional characterizations, leveraging novel adaptations of scRNAseq, and performing single-cell sorting and sequencing across neurodegenerative diseases and disease models. We focus on modeling neurodegeneration using glaucoma and other neurodegenerative pathologies to investigate the temporal and spatial dynamics of neurodegenerative disease pathogenesis, suggesting researchers aim to identify pan-neurodegenerative drug targets and drug combinations leverageable across neurodegenerative diseases.
{"title":"Modeling neurodegeneration in the retina and strategies for developing pan-neurodegenerative therapies","authors":"Emily L. Ward, Larry Benowitz, Thomas M. Brunner, Guojun Bu, Michel Cayouette, Valeria Canto‐Soler, Sandro Dá Mesquita, Adriana Di Polo, Aaron DiAntonio, Xin Duan, Jeffrey L. Goldberg, Zhigang He, Yang Hu, Shane A. Liddelow, Anna La Torre, Milica Margeta, Francisco Quintana, Karthik Shekhar, Beth Stevens, Sally Temple, Humsa Venkatesh, Derek Welsbie, John G. Flanagan","doi":"10.1186/s13024-025-00858-5","DOIUrl":"https://doi.org/10.1186/s13024-025-00858-5","url":null,"abstract":"Glaucoma Research Foundation's third Catalyst for a Cure team (CFC3) was established in 2019 to uncover new therapies for glaucoma, a leading cause of blindness. In the 2021 meeting “Solving Neurodegeneration,” (detailed in Mol Neurodegeneration 17(1), 2022) the team examined the failures of investigational monotherapies, issues with translatability, and other significant challenges faced when working with neurodegenerative disease models. They emphasized the need for novel, humanized models and proposed identifying commonalities across neurodegenerative diseases to support the creation of pan-neurodegenerative disease therapies. Since then, the fourth Catalyst for a Cure team (CFC4) was formed to explore commonalities between glaucoma and other neurodegenerative diseases. This review summarizes outcomes from the 2023 “Solving Neurodegeneration 2” meeting, a forum for CFC3 and CFC4 to share updates, problem solve, plan future research collaborations, and identify areas of unmet need or opportunity in glaucoma and the broader field of neurodegenerative disease research. We summarize the recent progress in the field of neurodegenerative disease research and present the newest challenges and opportunities moving forward. While translatability and disease complexity continue to pose major challenges, important progress has been made in identifying neuroprotective targets and understanding neuron-glia-vascular cell interactions. New challenges involve improving our understanding of the disease microenvironment and timeline, identifying the optimal approach(es) to neuronal replacement, and finding the best drug combinations and synergies for neuroprotection. We propose solutions to common research questions, provide prescriptive recommendations for future studies, and detail methodologies, strategies, and approaches for addressing major challenges at the forefront of neurodegenerative disease research. This review is intended to serve as a research framework, offering recommendations and approaches to validating neuroprotective targets, investigating rare cell types, performing cell-specific functional characterizations, leveraging novel adaptations of scRNAseq, and performing single-cell sorting and sequencing across neurodegenerative diseases and disease models. We focus on modeling neurodegeneration using glaucoma and other neurodegenerative pathologies to investigate the temporal and spatial dynamics of neurodegenerative disease pathogenesis, suggesting researchers aim to identify pan-neurodegenerative drug targets and drug combinations leverageable across neurodegenerative diseases. ","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"15 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145283439","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 : 2025-10-13DOI: 10.1186/s13024-025-00893-2
Livia La Barbera,Paraskevi Krashia,Gilda Loffredo,Emma Cauzzi,Maria Luisa De Paolis,Martina Montanari,Luana Saba,Elena Spoleti,Serena Ficchì,Claudio Zaccone,Marco De Bardi,Claudia Palazzo,Ramona Marino,Emanuele Claudio Latagliata,Stefano Puglisi-Allegra,Giovanna Borsellino,Flavio Keller,Luisa Lo Iacono,Maria Teresa Viscomi,Annalisa Nobili,Marcello D'Amelio
BACKGROUNDSmaller midbrain volumes predict Alzheimer's Disease (AD) progression and faster conversion from Mild Cognitive Impairment (MCI) to dementia. Along with this, various midbrain-target areas are characterized by neuroinflammation since the MCI stage. The concomitance of neuroinflammation, Αβ and tau appears to be a strong predictor for conversion from MCI to dementia. Yet, how midbrain degeneration could cause disease progression, and what mechanisms are involved in triggering neuroinflammation in midbrain-target areas such as the hippocampus remain unexplored.METHODSUsing adult C57BL/6N mice we generated a new mouse model carrying lesions in three midbrain nuclei, the dopaminergic Ventral Tegmental Area (VTA) and Substantia Nigra pars compacta (SNpc) and the serotonergic Interpeduncular Nucleus (IPN), to evaluate the consequences of dopamine and serotonin deprivation in midbrain-target areas. We characterized this model by performing stereological cell counts, analysis of monoaminergic fibers, monoamine levels, electrophysiology and behavioral tests. We then assessed hippocampal neuroinflammation by analyzing glia cell count, changes in morphology, NLRP3 inflammasome activation and cytokine levels, and microglia transcriptional profiling. In a separate set of experiments, we induced experimental midbrain lesion in Tg2576 transgenic mice overexpressing the Swedish mutant amyloid precursor protein, to evaluate the effect of monoamine deprivation on the hippocampus in concomitance with amyloid-β (Aβ) accumulation. The lesion performed in Tg2576 mice, as opposed to that in C57BL/6N mice, provides valuable insights into how neuroinflammation is influenced by Aβ accumulation versus the exclusive impact of impaired monoaminergic signaling.RESULTSThe concomitant depletion of dopaminergic and serotonergic inputs within the hippocampus of C57BL/6N mice provokes a pronounced activation of microglia via the NLRP3-inflammasome pathway, accompanied by increased IL-1β expression. Pharmacological intervention with either dopaminergic (L-DOPA or A68930) or serotonergic (fluoxetine) agents abrogates this neuroinflammatory response. In the Tg2576 transgenic mouse model of amyloid pathology, which exhibits progressive Aβ deposition, superimposed midbrain degeneration markedly amplifies AD-like neuropathology. This includes exacerbation of microglial reactivity, robust astrocyte response, precocious Aβ plaque burden, and induction of pathological tau hyperphosphorylation. Notably, administration of L-DOPA or fluoxetine significantly attenuates both the astrocyte reactivity and tau hyperphosphorylation in the lesioned Tg2576 cohort.CONCLUSIONSThese results highlight the pivotal role of midbrain damage for the amplification of neuroinflammatory cascades and AD pathology. Moreover, they offer mechanistic insight into the faster progression to dementia in patients with midbrain deficits. By translating these findings into clinical practice, we can advance toward
背景：较小的中脑容量预示着阿尔茨海默病（AD）的进展和从轻度认知障碍（MCI）到痴呆的更快转化。与此同时，自MCI阶段以来，各种中脑靶区以神经炎症为特征。神经炎症、Αβ和tau的共存似乎是MCI向痴呆转化的一个强有力的预测因子。然而，中脑变性如何导致疾病进展，以及在诸如海马等中脑靶区触发神经炎症的机制仍未被探索。方法以成年C57BL/6N小鼠为实验对象，建立了携带中脑3个核、多巴胺能腹侧被盖区（VTA）、黑质致密部（SNpc）和5 -羟色胺能脚间核（IPN）病变的小鼠模型，以评价多巴胺和5 -羟色胺剥夺对中脑靶区的影响。我们通过进行立体细胞计数、单胺能纤维分析、单胺水平、电生理和行为测试来表征该模型。然后，我们通过分析胶质细胞计数、形态学变化、NLRP3炎性体激活和细胞因子水平以及小胶质细胞转录谱来评估海马神经炎症。在另一组实验中，我们对过表达瑞典淀粉样蛋白突变体的Tg2576转基因小鼠进行实验性中脑损伤，以评估单胺剥夺对海马与淀粉样蛋白-β (a β)积累同时发生的影响。Tg2576小鼠的病变与C57BL/6N小鼠的病变相反，为神经炎症如何受到Aβ积累的影响而不是单胺能信号受损的唯一影响提供了有价值的见解。结果C57BL/6N小鼠海马内多巴胺能和5 -羟色胺能输入的消耗通过nlrp3 -炎性体途径引起小胶质细胞的明显激活，并伴有IL-1β表达的增加。多巴胺能（L-DOPA或A68930）或血清素能（氟西汀）药物干预可消除这种神经炎症反应。在Tg2576转基因小鼠淀粉样蛋白病理模型中，表现出进行性Aβ沉积，叠加的中脑变性明显放大ad样神经病理。这包括小胶质细胞反应性加剧，星形胶质细胞反应增强，Aβ斑块负担早熟，以及病理性tau过度磷酸化的诱导。值得注意的是，在受损的Tg2576队列中，左旋多巴或氟西汀可显著减弱星形胶质细胞的反应性和tau蛋白的过度磷酸化。结论中脑损伤在神经炎症级联扩增和AD病理中起关键作用。此外，它们为中脑缺陷患者更快发展为痴呆症提供了机制上的见解。通过将这些发现转化为临床实践，我们可以向疾病管理的精准医学方法迈进。
{"title":"Midbrain degeneration triggers astrocyte reactivity and tau pathology in experimental Alzheimer's Disease.","authors":"Livia La Barbera,Paraskevi Krashia,Gilda Loffredo,Emma Cauzzi,Maria Luisa De Paolis,Martina Montanari,Luana Saba,Elena Spoleti,Serena Ficchì,Claudio Zaccone,Marco De Bardi,Claudia Palazzo,Ramona Marino,Emanuele Claudio Latagliata,Stefano Puglisi-Allegra,Giovanna Borsellino,Flavio Keller,Luisa Lo Iacono,Maria Teresa Viscomi,Annalisa Nobili,Marcello D'Amelio","doi":"10.1186/s13024-025-00893-2","DOIUrl":"https://doi.org/10.1186/s13024-025-00893-2","url":null,"abstract":"BACKGROUNDSmaller midbrain volumes predict Alzheimer's Disease (AD) progression and faster conversion from Mild Cognitive Impairment (MCI) to dementia. Along with this, various midbrain-target areas are characterized by neuroinflammation since the MCI stage. The concomitance of neuroinflammation, Αβ and tau appears to be a strong predictor for conversion from MCI to dementia. Yet, how midbrain degeneration could cause disease progression, and what mechanisms are involved in triggering neuroinflammation in midbrain-target areas such as the hippocampus remain unexplored.METHODSUsing adult C57BL/6N mice we generated a new mouse model carrying lesions in three midbrain nuclei, the dopaminergic Ventral Tegmental Area (VTA) and Substantia Nigra pars compacta (SNpc) and the serotonergic Interpeduncular Nucleus (IPN), to evaluate the consequences of dopamine and serotonin deprivation in midbrain-target areas. We characterized this model by performing stereological cell counts, analysis of monoaminergic fibers, monoamine levels, electrophysiology and behavioral tests. We then assessed hippocampal neuroinflammation by analyzing glia cell count, changes in morphology, NLRP3 inflammasome activation and cytokine levels, and microglia transcriptional profiling. In a separate set of experiments, we induced experimental midbrain lesion in Tg2576 transgenic mice overexpressing the Swedish mutant amyloid precursor protein, to evaluate the effect of monoamine deprivation on the hippocampus in concomitance with amyloid-β (Aβ) accumulation. The lesion performed in Tg2576 mice, as opposed to that in C57BL/6N mice, provides valuable insights into how neuroinflammation is influenced by Aβ accumulation versus the exclusive impact of impaired monoaminergic signaling.RESULTSThe concomitant depletion of dopaminergic and serotonergic inputs within the hippocampus of C57BL/6N mice provokes a pronounced activation of microglia via the NLRP3-inflammasome pathway, accompanied by increased IL-1β expression. Pharmacological intervention with either dopaminergic (L-DOPA or A68930) or serotonergic (fluoxetine) agents abrogates this neuroinflammatory response. In the Tg2576 transgenic mouse model of amyloid pathology, which exhibits progressive Aβ deposition, superimposed midbrain degeneration markedly amplifies AD-like neuropathology. This includes exacerbation of microglial reactivity, robust astrocyte response, precocious Aβ plaque burden, and induction of pathological tau hyperphosphorylation. Notably, administration of L-DOPA or fluoxetine significantly attenuates both the astrocyte reactivity and tau hyperphosphorylation in the lesioned Tg2576 cohort.CONCLUSIONSThese results highlight the pivotal role of midbrain damage for the amplification of neuroinflammatory cascades and AD pathology. Moreover, they offer mechanistic insight into the faster progression to dementia in patients with midbrain deficits. By translating these findings into clinical practice, we can advance toward","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"11 1","pages":"105"},"PeriodicalIF":15.1,"publicationDate":"2025-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145277159","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 : 2025-10-13DOI: 10.1186/s13024-025-00899-w
Bjørn-Eivind Kirsebom, Johanna Nilsson, Ellen Vromen, Peter Mikael Arnesen, Atle Bjørnerud, Ann Brinkmalm, Geir Bråthen, Gøril Rolfseng Grøntvedt, Jonas Jarholm, Kaja Nordengen, Lene Pålhaugen, Per Selnes, Nikias Siafarikas, Ragnhild Eide Skogseth, Sandra Tecelão, Knut Waterloo, Panpan You, Henrik Zetterberg, Dag Aarsland, Betty Tijms, Pieter Jelle Visser, Kaj Blennow, Tormod Fladby
Synapse loss is linked to cognitive symptoms in Alzheimer’s Disease (AD) and Cerebrospinal fluid (CSF) synaptic biomarkers may clarify disease heterogeneity and disease mechanisms for progression beyond amyloid (Aβ) and tau pathologies, potentially revealing new drug targets. We used a mass-spectrometry panel of 17 synaptic biomarkers including neuronal pentraxins (NPTXs) linked to glutamatergic signaling, and 14-3-3 proteins linked to tau-pathology and synaptic plasticity. Synapse markers were evaluated in two independent cohorts: Dementia Disease Initiation (DDI) (n = 346) and Amsterdam Dementia Cohort (n = 397), both with cognitive assessments up to 10 years. We used linear regression to compare synapse marker differences between CSF-determined Aβ + cognitively normal (CN) and Mild Cognitive Impairment (MCI) groups, with or without CSF tau pathology (Tau+/-), relative to CN Aβ-/Tau- controls; and associations between synapse markers and medial temporal lobe (MTL) MRI volumetrics in the DDI cohort and with verbal memory in both cohorts. A funneling procedure identified proteins related to Aβ/Tau pathology and memory impairment in both cohorts, which were used to evaluate relations to Aβ/Tau biological progression in the DDI cohort and memory decline in both cohorts. Finally, we explored genetic pathways associated with these synaptic proteins. In both cohorts, most markers were elevated in Aβ+/Tau + cases compared to controls, particularly 14-3-3ζ/δ. Several proteins were reduced in Aβ+/Tau- cases, especially NPTX-2, while 14-3-3ζ/δ remained elevated. However, the increase in e.g. 14-3-3ζ/δ and reduction in e.g. NPTX2 were more pronounced in patients with MCI than CN cases regardless of tau-pathology, corresponding to verbal memory impairment and MTL atrophy. Elevated baseline 14-3-3ζ/δ and rab GDP Dissociation Inhibitor Alpha (GDI-1) associated with future progression from Aβ+/Tau- to Aβ+/Tau+. Significant associations (all p < 0.001) were found between 14-3-3 protein genes (YWHAZ, YWHAE) and pathways linked to AD, including the p38 MAPK, IGF, PIK3/AKT and between GDI1 and p38 MAPK upstream pathway (p < 0.05) all connected to synaptic plasticity. Correspondingly, a robust 14-3-3ζ/δ association with future memory decline was observed in both cohorts. Reduced markers for excitatory signaling in Aβ+/Tau- and increased synaptic plasticity markers in Aβ+/Tau + cases suggest differential but linked processes underlying disease progression and resilience in the groups.
{"title":"Cerebrospinal fluid markers link to synaptic plasticity responses and Alzheimer’s disease genetic pathways","authors":"Bjørn-Eivind Kirsebom, Johanna Nilsson, Ellen Vromen, Peter Mikael Arnesen, Atle Bjørnerud, Ann Brinkmalm, Geir Bråthen, Gøril Rolfseng Grøntvedt, Jonas Jarholm, Kaja Nordengen, Lene Pålhaugen, Per Selnes, Nikias Siafarikas, Ragnhild Eide Skogseth, Sandra Tecelão, Knut Waterloo, Panpan You, Henrik Zetterberg, Dag Aarsland, Betty Tijms, Pieter Jelle Visser, Kaj Blennow, Tormod Fladby","doi":"10.1186/s13024-025-00899-w","DOIUrl":"https://doi.org/10.1186/s13024-025-00899-w","url":null,"abstract":"Synapse loss is linked to cognitive symptoms in Alzheimer’s Disease (AD) and Cerebrospinal fluid (CSF) synaptic biomarkers may clarify disease heterogeneity and disease mechanisms for progression beyond amyloid (Aβ) and tau pathologies, potentially revealing new drug targets. We used a mass-spectrometry panel of 17 synaptic biomarkers including neuronal pentraxins (NPTXs) linked to glutamatergic signaling, and 14-3-3 proteins linked to tau-pathology and synaptic plasticity. Synapse markers were evaluated in two independent cohorts: Dementia Disease Initiation (DDI) (n = 346) and Amsterdam Dementia Cohort (n = 397), both with cognitive assessments up to 10 years. We used linear regression to compare synapse marker differences between CSF-determined Aβ + cognitively normal (CN) and Mild Cognitive Impairment (MCI) groups, with or without CSF tau pathology (Tau+/-), relative to CN Aβ-/Tau- controls; and associations between synapse markers and medial temporal lobe (MTL) MRI volumetrics in the DDI cohort and with verbal memory in both cohorts. A funneling procedure identified proteins related to Aβ/Tau pathology and memory impairment in both cohorts, which were used to evaluate relations to Aβ/Tau biological progression in the DDI cohort and memory decline in both cohorts. Finally, we explored genetic pathways associated with these synaptic proteins. In both cohorts, most markers were elevated in Aβ+/Tau + cases compared to controls, particularly 14-3-3ζ/δ. Several proteins were reduced in Aβ+/Tau- cases, especially NPTX-2, while 14-3-3ζ/δ remained elevated. However, the increase in e.g. 14-3-3ζ/δ and reduction in e.g. NPTX2 were more pronounced in patients with MCI than CN cases regardless of tau-pathology, corresponding to verbal memory impairment and MTL atrophy. Elevated baseline 14-3-3ζ/δ and rab GDP Dissociation Inhibitor Alpha (GDI-1) associated with future progression from Aβ+/Tau- to Aβ+/Tau+. Significant associations (all p < 0.001) were found between 14-3-3 protein genes (YWHAZ, YWHAE) and pathways linked to AD, including the p38 MAPK, IGF, PIK3/AKT and between GDI1 and p38 MAPK upstream pathway (p < 0.05) all connected to synaptic plasticity. Correspondingly, a robust 14-3-3ζ/δ association with future memory decline was observed in both cohorts. Reduced markers for excitatory signaling in Aβ+/Tau- and increased synaptic plasticity markers in Aβ+/Tau + cases suggest differential but linked processes underlying disease progression and resilience in the groups.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"38 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145277422","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}
<p><b>Correction to: Molecular Neurodegeneration (2025) 20:90</b></p><p><b>https://doi.org/10.1186/s13024-025-00879-0</b></p><p>The original article has been updated to correct the framing of Figs. 1 and 2, as well as to restore the legend of Fig. 2 which was mistakenly incorporated into the main body text.</p><span>Author notes</span><ol><li><p>Jingfeng Liang and Rongzhen Li have contributed equally to this work.</p></li></ol><h3>Authors and Affiliations</h3><ol><li><p>College of Pharmacy, Shenzhen Technology University, Shenzhen, 518000, China</p><p>Jingfeng Liang & Xiaobing Huang</p></li><li><p>Department of Neurology, Baiyun District People’s Hospital of Guangzhou, Guangzhou, 510000, China</p><p>Jingfeng Liang</p></li><li><p>Department of Global Public Health and Medicinal Administration, Faculty of Health Sciences, University of Macau, Macau S.A.R, 999078, China</p><p>Rongzhen Li & Garry Wong</p></li></ol><span>Authors</span><ol><li><span>Jingfeng Liang</span>View author publications<p><span>Search author on:</span><span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Rongzhen Li</span>View author publications<p><span>Search author on:</span><span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Garry Wong</span>View author publications<p><span>Search author on:</span><span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Xiaobing Huang</span>View author publications<p><span>Search author on:</span><span>PubMed<span> </span>Google Scholar</span></p></li></ol><h3>Corresponding author</h3><p>Correspondence to Xiaobing Huang.</p><h3>Publisher’s note</h3><p>Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.</p><p><b>Open Access</b> This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.</p> <p>Reprints and permissions</p><img alt="Check for updates. Verify currency and authenticity via CrossMark" height="81" loading="lazy" src="data:image/svg+xml;base64,PHN2ZyBoZ
{"title":"Correction: 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/s13024-025-00902-4","DOIUrl":"https://doi.org/10.1186/s13024-025-00902-4","url":null,"abstract":"<p><b>Correction to: Molecular Neurodegeneration (2025) 20:90</b></p><p><b>https://doi.org/10.1186/s13024-025-00879-0</b></p><p>The original article has been updated to correct the framing of Figs. 1 and 2, as well as to restore the legend of Fig. 2 which was mistakenly incorporated into the main body text.</p><span>Author notes</span><ol><li><p>Jingfeng Liang and Rongzhen Li have contributed equally to this work.</p></li></ol><h3>Authors and Affiliations</h3><ol><li><p>College of Pharmacy, Shenzhen Technology University, Shenzhen, 518000, China</p><p>Jingfeng Liang & Xiaobing Huang</p></li><li><p>Department of Neurology, Baiyun District People’s Hospital of Guangzhou, Guangzhou, 510000, China</p><p>Jingfeng Liang</p></li><li><p>Department of Global Public Health and Medicinal Administration, Faculty of Health Sciences, University of Macau, Macau S.A.R, 999078, China</p><p>Rongzhen Li & Garry Wong</p></li></ol><span>Authors</span><ol><li><span>Jingfeng Liang</span>View author publications<p><span>Search author on:</span><span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Rongzhen Li</span>View author publications<p><span>Search author on:</span><span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Garry Wong</span>View author publications<p><span>Search author on:</span><span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Xiaobing Huang</span>View author publications<p><span>Search author on:</span><span>PubMed<span> </span>Google Scholar</span></p></li></ol><h3>Corresponding author</h3><p>Correspondence to Xiaobing Huang.</p><h3>Publisher’s note</h3><p>Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.</p><p><b>Open Access</b> This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.</p>\u0000<p>Reprints and permissions</p><img alt=\"Check for updates. Verify currency and authenticity via CrossMark\" height=\"81\" loading=\"lazy\" src=\"data:image/svg+xml;base64,PHN2ZyBoZ","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"69 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145255688","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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