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":"<p><p>BACKGROUND: Synapse function is critical for cognition, and synapse loss is highly correlated with cognitive decline in Alzheimer’s disease and related dementias. Tau oligomers, which accumulate in the brain in Alzheimer’s disease, can acutely inhibit synaptic plasticity and cause synapse loss. Coordinated presynaptic and postsynaptic function is essential for effective synaptic transmission, and both compartments can be dysregulated by pathogenic tau. However, the series of pathophysiological events triggered by tau oligomers to cause the dysfunction and deterioration of presynaptic terminals and postsynaptic sites remain unclear. METHODS: We developed a proximity labeling tool to map the postsynaptic proteome by fusing PSD-95 with APEX2 (APEX2-PSD-95) which was expressed in human induced pluripotent stem cell (iPSC)-derived neurons. We used APEX2-PSD-95 to map the dynamic changes in the postsynaptic proteome with precise temporal resolution after an acute exposure of human iPSC-derived neurons to recombinant tau oligomers for 30 min. Leveraging immunocytochemistry, electrophysiology and electron microscopy, we further delineated the impact of the acute tau oligomer exposure on presynaptic and postsynaptic compartments over time for up to 14 days. RESULTS: The brief exposure of human iPSC-derived neurons to tau oligomers caused a progressive deterioration of synapses, marked by both presynaptic and postsynaptic dysregulation. Postsynaptic proteome mapping revealed an immediate tau oligomer-triggered downregulation of the postsynaptic actin motor proteins Myosin-Va and Myosin IIb, which coincided with impaired AMPA receptor (AMPAR) trafficking during synaptic plasticity. This was followed 24 h later by the upregulation of disease-related proteins, including GSK3β, at postsynaptic sites. The loss of PSD-95-labeled postsynaptic sites at 7 days after tau oligomer exposure preceded the loss of Synapsin-labeled presynaptic terminals at 14 days. The postsynaptic sites that remained exhibited a long-term downregulation of postsynaptic AMPAR levels and sustained synaptic plasticity impairment. Moreover, the remaining presynaptic terminals contained less clusters of vesicles at the presynaptic active zone which was associated with reduced vesicle release probability at synapses. CONCLUSION: Our findings reveal the series of events underlying tau oligomer-induced bipartite synapse deterioration. The progressive decline of synapses involves the emergence of two synapse fates. One synapse fate involves the persistent weakening of both presynaptic and postsynaptic function, and the other results in synaptic loss.</p>","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":" ","pages":"13"},"PeriodicalIF":19.6,"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}
{"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}
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}
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
{"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}
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":"<p><p>BACKGROUND: Motor symptoms of Parkinson’s disease (PD) primarily result from the degeneration of nigrostriatal dopaminergic neurons (DANs), particularly the Aldehyde Dehydrogenase 1A1-positive (ALDH1A1⁺) subpopulation. Pitx3-deficient mice exhibit selective developmental loss of ALDH1A1⁺ DANs but paradoxically display hyperlocomotion, suggesting compensatory changes in striatal circuitry. The dorsal striatum contains four main types of spiny projection neurons (SPNs): patch (or striosome) and matrix subtypes of both direct-pathway (dSPNs) and indirect-pathway (iSPNs). Activation of patch dSPNs suppresses locomotion by inhibiting ALDH1A1⁺ DANs. METHODS: We combined RNAscope in situ hybridization with SPN subtype-specific reporter mice to quantify patch and total dSPNs and iSPNs in Pitx3-deficient and control mice. Three patch SPN reporter lines (Kremen12A − Cre, Nr4a1-GFP, and PdynIRES−Cre) were used to map projections. Optogenetic stimulation was performed in freely moving mice to assess the behavioral effects of activating patch dSPNs and iSPNs. RESULTS: Pitx3-deficient mice showed no change in the overall dSPN: iSPN ratio but exhibited a marked shift in the patch dSPN: patch iSPN ratio, which decreased from 1.7 in control mice to 0.7 in the Pitx3-deficient group. Accordingly, patch dSPN projections to the substantia nigra pars reticulata (SNr) were reduced, whereas patch iSPN projections to the globus pallidus externus (GPe) were enhanced. Notably, while optogenetic stimulation of patch dSPNs and iSPNs suppressed locomotion in control mice, the same stimulation promoted locomotion in Pitx3-deficient mice. CONCLUSIONS: Our findings reveal a selective reorganization of patch SPNs in response to developmental loss of ALDH1A1⁺ DANs, characterized by reduced patch dSPN and enhanced patch iSPN influence. This shift may underlie the paradoxical hyperlocomotion observed in Pitx3-deficient mice and provides insight into circuit-level adaptations with potential therapeutic relevance for PD.</p>","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":" ","pages":"7"},"PeriodicalIF":19.6,"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}
{"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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