Pub Date : 2026-01-22DOI: 10.1186/s13024-026-00928-2
Kristeen A Pareja-Navarro, Christina D King, Grant Kauwe, Yani Y Ngwala, Doyle Lokitiyakul, Ivy Wong, Aaryan Vira, Yaofu Liu, Jackson H Chen, Mahima Sharma, Gabriel Navarro, Olfat Malak, Chuankai Zhou, Birgit Schilling, Tara E Tracy
{"title":"Tau oligomers modulate synapse fate by eliciting progressive bipartite synapse dysregulation and synapse loss.","authors":"Kristeen A Pareja-Navarro, Christina D King, Grant Kauwe, Yani Y Ngwala, Doyle Lokitiyakul, Ivy Wong, Aaryan Vira, Yaofu Liu, Jackson H Chen, Mahima Sharma, Gabriel Navarro, Olfat Malak, Chuankai Zhou, Birgit Schilling, Tara E Tracy","doi":"10.1186/s13024-026-00928-2","DOIUrl":"10.1186/s13024-026-00928-2","url":null,"abstract":"","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":" ","pages":"13"},"PeriodicalIF":17.5,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12918473/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146030029","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}
BACKGROUNDComplement dysregulation is increasingly recognized in Alzheimer's disease (AD). However, the temporal profile of complement alterations preceding AD onset and their distinction from age-related immune changes remain poorly defined. Clarifying these dynamics could provide insights into AD pathogenesis and identify systemic factors that predict disease onset and progression.METHODSWe conducted a study involving two cohorts: a longitudinal cohort (n = 235; all cognitively normal at baseline) and a cross-sectional cohort (n = 323; including 53 with AD, 54 with vascular dementia, 51 with Parkinson's disease dementia, 56 with behavioral variant frontotemporal dementia, and 52 with dementia with Lewy bodies). Plasma levels of 14 complement factors were assessed every 2 years over a 10-year follow-up period in the longitudinal cohort and once in the cross-sectional cohort.RESULTSIn the longitudinal cohort, aging was accompanied by gradual reductions in C4, C4b, Factor I, and Properdin and by increases in Factor D. These changes were more pronounced in individuals who subsequently developed AD. Importantly, this pattern of complement alterations was detectable during the preclinical and clinical phases of AD but was not observed in other dementias. In the cross-sectional cohort, the same complement profile was specific to AD and distinguished it from other dementia subtypes.CONCLUSIONSThe results of this study indicate an AD-specific peripheral complement signature associated with disease development, highlighting complement factors as critical immune mediators that link aging and AD. This signature implicates complement factors as promising systemic markers for early detection and potential therapeutic targeting in preclinical AD.
{"title":"Systemic complement factors in aging, Alzheimer's disease and other dementias: a longitudinal study over 10 years.","authors":"Xiaofeng Fu,Huimin Cai,Shuiyue Quan,Weiyun Zhang,Yumei Geng,Qing Tian,Ziye Ren,Yinghao Xu,Chengyu An,Jiaqi Li,Changbiao Chu,Wei Wang,Yana Pang,QianQian Wang,Lu Lu,Qi Wang,Yan Li,Fangyu Li,Shuya Nie,Longfei Jia","doi":"10.1186/s13024-026-00927-3","DOIUrl":"https://doi.org/10.1186/s13024-026-00927-3","url":null,"abstract":"BACKGROUNDComplement dysregulation is increasingly recognized in Alzheimer's disease (AD). However, the temporal profile of complement alterations preceding AD onset and their distinction from age-related immune changes remain poorly defined. Clarifying these dynamics could provide insights into AD pathogenesis and identify systemic factors that predict disease onset and progression.METHODSWe conducted a study involving two cohorts: a longitudinal cohort (n = 235; all cognitively normal at baseline) and a cross-sectional cohort (n = 323; including 53 with AD, 54 with vascular dementia, 51 with Parkinson's disease dementia, 56 with behavioral variant frontotemporal dementia, and 52 with dementia with Lewy bodies). Plasma levels of 14 complement factors were assessed every 2 years over a 10-year follow-up period in the longitudinal cohort and once in the cross-sectional cohort.RESULTSIn the longitudinal cohort, aging was accompanied by gradual reductions in C4, C4b, Factor I, and Properdin and by increases in Factor D. These changes were more pronounced in individuals who subsequently developed AD. Importantly, this pattern of complement alterations was detectable during the preclinical and clinical phases of AD but was not observed in other dementias. In the cross-sectional cohort, the same complement profile was specific to AD and distinguished it from other dementia subtypes.CONCLUSIONSThe results of this study indicate an AD-specific peripheral complement signature associated with disease development, highlighting complement factors as critical immune mediators that link aging and AD. This signature implicates complement factors as promising systemic markers for early detection and potential therapeutic targeting in preclinical AD.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"47 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145956054","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 : 2026-01-06DOI: 10.1186/s13024-025-00919-9
Gabriella A Perez,Zoe Lai,George A Edwards Iii,Jacob M Dundee,Shannon N Leahy,Chuangye Qi,Yanyan Qi,Ye-Jin Park,Tzu-Chiao Lu,M Danish Uddin,Rong Zhao,Hui Zheng,Hongjie Li,Joanna L Jankowsky
{"title":"Neuronal subtype governs amyloid structure, cellular response, and cognitive outcome in genetically targeted APP mouse models.","authors":"Gabriella A Perez,Zoe Lai,George A Edwards Iii,Jacob M Dundee,Shannon N Leahy,Chuangye Qi,Yanyan Qi,Ye-Jin Park,Tzu-Chiao Lu,M Danish Uddin,Rong Zhao,Hui Zheng,Hongjie Li,Joanna L Jankowsky","doi":"10.1186/s13024-025-00919-9","DOIUrl":"https://doi.org/10.1186/s13024-025-00919-9","url":null,"abstract":"","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"15 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145907800","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 : 2026-01-05DOI: 10.1186/s13024-025-00921-1
Michael R Duggan,Hamilton Se-Hwee Oh,Philipp Frank,Gabriela T Gomez,David Zweibaum,Yuhan Cui,Jingsha Chen,Aditya Surapaneni,Cassandra O Blew,Heather E Dark,Cassandra M Joynes,Sridhar Kandala,Murat Bilgel,Amelia Farinas,Guray Erus,Qu Tian,Julián Candia,Krishna A Pucha,Bennett A Landman,Logan Dumitrescu,Timothy J Hohman,Alexandria Lewis,Abhay Moghekar,Fatemeh Siavoshi,Muhammad Ali,Menghan Liu,Ying Xu,Daniel Western,Naoto Kaneko,Shintaro Kato,Makio Furuichi,Masaki Shibayama,Masahisa Katsuno,Yukiko Nishita,Rei Otsuka,Rebecca F Gottesman,Eric B Dammer,Nicholas T Seyfried,Allan I Levey,Erik C B Johnson,Elizabeth Mormino,Anthony D Wagner,Kathleen L Poston,Dimitrios Kapogiannis,Morgan E Grams,Pavan Bhargava,Iwao Waga,Christos Davatzikos,Susan M Resnick,Luigi Ferrucci,David A Bennett,Carlos Cruchaga,Tony Wyss-Coray,Mika Kivimäki,Josef Coresh,Keenan A Walker
BACKGROUNDBiofluid proteomics can enhance our understanding of the neurodegenerative mechanisms underlying Alzheimer's disease and related dementias (ADRDs). Oligodendrocyte myelin glycoprotein (OMG) is a brain-specific protein implicated in myelination, but its potential mechanistic, biomarker, and therapeutic roles in ADRDs requires further elucidation.METHODSAfter detecting an inverse association between its abundance in peripheral circulation and cortical amyloid deposition in two community-based cohorts, the current study characterized OMG's role in ADRDs with high-throughput proteomics from sixteen independent cohorts. Data included a variety of cross-sectional and longitudinal community-based and clinical cohorts from North America, Europe, and Asia, and incorporated complementary biofluids, biospecimens, and proteomic platforms. Statistical analyses were conducted separately in each cohort.RESULTSWe detected lower plasma OMG in individuals with cortical amyloid deposition, compromised brain structure, dementia, and multiple sclerosis, as well as in individuals who developed dementia over 7- to 20-year follow-up periods. OMG's CSF and brain proteomic signatures reflected broader neuroprotective mechanisms, especially axonal structural integrity, and two-sample Mendelian randomization causally implicated OMG as protective against multiple neurodegenerative diseases.CONCLUSIONSOur findings implicate OMG as a mechanistic determinant of neurodegenerative resiliency among older adults, which is reliably captured by its abundance in peripheral circulation.
{"title":"OMG! A proteomic determinant of neurodegenerative resiliency.","authors":"Michael R Duggan,Hamilton Se-Hwee Oh,Philipp Frank,Gabriela T Gomez,David Zweibaum,Yuhan Cui,Jingsha Chen,Aditya Surapaneni,Cassandra O Blew,Heather E Dark,Cassandra M Joynes,Sridhar Kandala,Murat Bilgel,Amelia Farinas,Guray Erus,Qu Tian,Julián Candia,Krishna A Pucha,Bennett A Landman,Logan Dumitrescu,Timothy J Hohman,Alexandria Lewis,Abhay Moghekar,Fatemeh Siavoshi,Muhammad Ali,Menghan Liu,Ying Xu,Daniel Western,Naoto Kaneko,Shintaro Kato,Makio Furuichi,Masaki Shibayama,Masahisa Katsuno,Yukiko Nishita,Rei Otsuka,Rebecca F Gottesman,Eric B Dammer,Nicholas T Seyfried,Allan I Levey,Erik C B Johnson,Elizabeth Mormino,Anthony D Wagner,Kathleen L Poston,Dimitrios Kapogiannis,Morgan E Grams,Pavan Bhargava,Iwao Waga,Christos Davatzikos,Susan M Resnick,Luigi Ferrucci,David A Bennett,Carlos Cruchaga,Tony Wyss-Coray,Mika Kivimäki,Josef Coresh,Keenan A Walker","doi":"10.1186/s13024-025-00921-1","DOIUrl":"https://doi.org/10.1186/s13024-025-00921-1","url":null,"abstract":"BACKGROUNDBiofluid proteomics can enhance our understanding of the neurodegenerative mechanisms underlying Alzheimer's disease and related dementias (ADRDs). Oligodendrocyte myelin glycoprotein (OMG) is a brain-specific protein implicated in myelination, but its potential mechanistic, biomarker, and therapeutic roles in ADRDs requires further elucidation.METHODSAfter detecting an inverse association between its abundance in peripheral circulation and cortical amyloid deposition in two community-based cohorts, the current study characterized OMG's role in ADRDs with high-throughput proteomics from sixteen independent cohorts. Data included a variety of cross-sectional and longitudinal community-based and clinical cohorts from North America, Europe, and Asia, and incorporated complementary biofluids, biospecimens, and proteomic platforms. Statistical analyses were conducted separately in each cohort.RESULTSWe detected lower plasma OMG in individuals with cortical amyloid deposition, compromised brain structure, dementia, and multiple sclerosis, as well as in individuals who developed dementia over 7- to 20-year follow-up periods. OMG's CSF and brain proteomic signatures reflected broader neuroprotective mechanisms, especially axonal structural integrity, and two-sample Mendelian randomization causally implicated OMG as protective against multiple neurodegenerative diseases.CONCLUSIONSOur findings implicate OMG as a mechanistic determinant of neurodegenerative resiliency among older adults, which is reliably captured by its abundance in peripheral circulation.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"21 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145903702","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 : 2026-01-03DOI: 10.1186/s13024-025-00920-2
Jie Dong, Breanna T Sullivan, Victor M Martinez Smith, Lupeng Wang, Lulu Tian, Justin Kung, Bin Song, Shirong Lin, Andreanna Le, Lixin Sun, Lisa Chang, Jinhui Ding, Weidong Le, Jun Jia, Huaibin Cai
{"title":"Developmental dopamine loss rewires striatal circuits to promote locomotion.","authors":"Jie Dong, Breanna T Sullivan, Victor M Martinez Smith, Lupeng Wang, Lulu Tian, Justin Kung, Bin Song, Shirong Lin, Andreanna Le, Lixin Sun, Lisa Chang, Jinhui Ding, Weidong Le, Jun Jia, Huaibin Cai","doi":"10.1186/s13024-025-00920-2","DOIUrl":"10.1186/s13024-025-00920-2","url":null,"abstract":"","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":" ","pages":"7"},"PeriodicalIF":17.5,"publicationDate":"2026-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12866494/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145896170","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}
Pub Date : 2025-12-22DOI: 10.1186/s13024-025-00918-w
Di Hu,Xiaoyan Sun,Xin Qi
BACKGROUNDMitochondrial dysfunction and α-Synuclein (αSyn) aggregation are defining features of Parkinson's disease (PD), yet the mechanistic link between them remains poorly understood. Although our previous findings suggest that the interaction between αSyn and ClpP (a mitochondrial matrix protease) contributes to PD progression, the pathogenic and therapeutic relevance of this interaction remains elusive.METHODSWe employed biochemical and cell biological approaches to investigate how αSyn and ClpP are mutually regulated. Additionally, we determined the pathogenic impact of αSyn-ClpP interaction by using decoy peptide CS2 in αSyn-PFF inoculated primary neurons, PD patient iPSC-derived dopaminergic neurons, and a transgenic mouse model of PD carrying αSyn-A53T mutation.RESULTSWe identified mitochondrial protease ClpP as a key regulator of αSyn pathology. We show that αSyn interacts with ClpP through its non-amyloid-β component (NAC) domain, leading to impaired ClpP activity and mitochondrial proteotoxic stress. ClpP, in turn, negatively regulates αSyn aggregation and propagation by stabilizing its native tetrameric form. To interrupt this pathogenic interaction, we developed a decoy peptide, CS2, which binds the NAC domain of αSyn and restores ClpP function. CS2 treatment reduced mitochondrial oxidative stress and αSyn neurotoxicity in neuronal cultures, primary cortical neurons inoculated with αSyn preformed fibrils, and dopaminergic neurons derived from PD patient iPSCs. In mThy1-hSNCA transgenic mice, subcutaneous administration of CS2 restored ClpP levels, decreased αSyn pathology and neuroinflammation, and improved both cognitive and motor function.CONCLUSIONThese findings highlight the αSyn-ClpP interaction as a druggable target and support CS2 as a potential disease-modifying therapy for PD and related synucleinopathies.
{"title":"Disrupting α-Synuclein-ClpP interaction restores mitochondrial function and attenuates neuropathology in Parkinson's disease models.","authors":"Di Hu,Xiaoyan Sun,Xin Qi","doi":"10.1186/s13024-025-00918-w","DOIUrl":"https://doi.org/10.1186/s13024-025-00918-w","url":null,"abstract":"BACKGROUNDMitochondrial dysfunction and α-Synuclein (αSyn) aggregation are defining features of Parkinson's disease (PD), yet the mechanistic link between them remains poorly understood. Although our previous findings suggest that the interaction between αSyn and ClpP (a mitochondrial matrix protease) contributes to PD progression, the pathogenic and therapeutic relevance of this interaction remains elusive.METHODSWe employed biochemical and cell biological approaches to investigate how αSyn and ClpP are mutually regulated. Additionally, we determined the pathogenic impact of αSyn-ClpP interaction by using decoy peptide CS2 in αSyn-PFF inoculated primary neurons, PD patient iPSC-derived dopaminergic neurons, and a transgenic mouse model of PD carrying αSyn-A53T mutation.RESULTSWe identified mitochondrial protease ClpP as a key regulator of αSyn pathology. We show that αSyn interacts with ClpP through its non-amyloid-β component (NAC) domain, leading to impaired ClpP activity and mitochondrial proteotoxic stress. ClpP, in turn, negatively regulates αSyn aggregation and propagation by stabilizing its native tetrameric form. To interrupt this pathogenic interaction, we developed a decoy peptide, CS2, which binds the NAC domain of αSyn and restores ClpP function. CS2 treatment reduced mitochondrial oxidative stress and αSyn neurotoxicity in neuronal cultures, primary cortical neurons inoculated with αSyn preformed fibrils, and dopaminergic neurons derived from PD patient iPSCs. In mThy1-hSNCA transgenic mice, subcutaneous administration of CS2 restored ClpP levels, decreased αSyn pathology and neuroinflammation, and improved both cognitive and motor function.CONCLUSIONThese findings highlight the αSyn-ClpP interaction as a druggable target and support CS2 as a potential disease-modifying therapy for PD and related synucleinopathies.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"20 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145807655","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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