Synucleinopathy is the most common co-pathology in Alzheimer's disease (AD) and can be detected in vivo using cerebrospinal fluid (CSF) alpha-synuclein seed amplification assays (synSAA). CSF synSAA positivity has been linked to worse clinical outcome. This study investigated whether synSAA positivity is also associated with levels of plasma neurofilament light chain (NfL), a sensitive, unspecific marker of neurodegeneration.
Methods
We retrospectively analyzed a cohort of 240 individuals across the AD clinical continuum who had undergone clinical, neuropsychological, and biomarker assessments including CSF synSAA. Analyses involving plasma NfL were conducted in the subgroup with available plasma samples collected at the time of lumbar puncture (n = 166). One-way and two-way ANOVA were used to compare log-transformed NfL levels among AD stages, according to synSAA status. Logistic regression models examined associations between log-transformed NfL and synSAA status, adjusting for age and AD stage.
Findings
No significant age difference was found between synSAA-positive and negative groups. Plasma NfL levels were significantly higher in synSAA-positive individuals. This association remained significant after adjusting for age and AD clinical stage.
Interpretation
In AD patients, CSF synSAA positivity is associated with increase of plasma NfL levels along the AD clinical continuum. This finding supports the knowledge that synuclein co-pathology represents a contributive factor of neurodegeneration in AD patients.
{"title":"Cerebrospinal fluid α-synuclein seed amplification assay positivity is associated with increased plasma neurofilament light chain in Alzheimer's disease","authors":"Giovanni Bellomo PhD , Andrea Toja MD , Lorenzo Gaetani MD, PhD , Giovanna Nardi MD , Federico Paolini Paoletti MD, PhD , Davide Chiasserini PhD , Lucilla Parnetti MD, PhD","doi":"10.1016/j.nbd.2025.107234","DOIUrl":"10.1016/j.nbd.2025.107234","url":null,"abstract":"<div><h3>Background</h3><div>Synucleinopathy is the most common co-pathology in Alzheimer's disease (AD) and can be detected in vivo using cerebrospinal fluid (CSF) alpha-synuclein seed amplification assays (synSAA). CSF synSAA positivity has been linked to worse clinical outcome. This study investigated whether synSAA positivity is also associated with levels of plasma neurofilament light chain (NfL), a sensitive, unspecific marker of neurodegeneration.</div></div><div><h3>Methods</h3><div>We retrospectively analyzed a cohort of 240 individuals across the AD clinical continuum who had undergone clinical, neuropsychological, and biomarker assessments including CSF synSAA. Analyses involving plasma NfL were conducted in the subgroup with available plasma samples collected at the time of lumbar puncture (<em>n</em> = 166). One-way and two-way ANOVA were used to compare log-transformed NfL levels among AD stages, according to synSAA status. Logistic regression models examined associations between log-transformed NfL and synSAA status, adjusting for age and AD stage.</div></div><div><h3>Findings</h3><div>No significant age difference was found between synSAA-positive and negative groups. Plasma NfL levels were significantly higher in synSAA-positive individuals. This association remained significant after adjusting for age and AD clinical stage.</div></div><div><h3>Interpretation</h3><div>In AD patients, CSF synSAA positivity is associated with increase of plasma NfL levels along the AD clinical continuum. This finding supports the knowledge that synuclein co-pathology represents a contributive factor of neurodegeneration in AD patients.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"218 ","pages":"Article 107234"},"PeriodicalIF":5.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145828016","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-01DOI: 10.1016/j.nbd.2025.107247
Jose A. Viteri , Nathan R. Kerr , Charles D. Brennan , Priyanka Paradkar , Leena A. Suleiman , Charles D. Wendt , Chunhui Xu , Hong An , Meifang Wang , Hiroshi Nishimune , Joseph M. Santin , W. David Arnold
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by spinal and cortical motor neuron loss and progressive neuromuscular decline. When ALS pathology involves the primary motor cortex (PMC), cortical excitability is often disrupted, yet how these alterations map onto motor deficits during symptomatic ALS remains unclear.
To investigate this, we examined the neuromuscular function, cortico-muscular output, and neuronal excitability of symptomatic 4-month-old TDP-43Q331K mice. TDP-43 mice exhibited reduced neuromuscular excitability and impaired strength compared to WT mice. Cranial motor evoked potentials were significantly reduced in TDP-43 mice, indicating decreased cortical output to muscle. Compared to WT mice, whole-cell patch-clamp recordings from TDP-43 PMC layer V pyramidal neurons revealed intrinsic hypoexcitability, diminished persistent inward currents (PICs), and decreased excitatory synaptic activity. Corroborating PIC findings, immunohistochemical analysis showed that PMC layer V neurons exhibited reduced signal intensity of the PIC-associated proteins Nav1.6 and 5-HT2C.
Bulk RNA-seq of the cortex showed distinct transcriptional profiles in TDP-43 mice, with enrichment analysis indicating altered pathways relating to ion transport, synaptic signaling, and neuronal excitability. These results suggest that cortex-wide transcriptional changes may reflect broader and additional molecular mechanisms underlying cortical hypoexcitability in ALS.
Together, our results demonstrate that symptomatic TDP-43Q331K mice exhibit a reduction in cortico-muscular output and PMC neuron excitability, accompanied by reduced PICs and PIC-associated proteins within these neurons. These findings identify cortical hypoexcitability as a defining feature of the TDP-43Q331k ALS mouse model and establish multi-level associations between cortical cellular-level dysfunction and impaired motor systems output.
{"title":"Reduced cortico-muscular output is associated with intrinsic hypoexcitability and reduced persistent inward currents in motor cortex neurons of TDP-43Q331K ALS mice","authors":"Jose A. Viteri , Nathan R. Kerr , Charles D. Brennan , Priyanka Paradkar , Leena A. Suleiman , Charles D. Wendt , Chunhui Xu , Hong An , Meifang Wang , Hiroshi Nishimune , Joseph M. Santin , W. David Arnold","doi":"10.1016/j.nbd.2025.107247","DOIUrl":"10.1016/j.nbd.2025.107247","url":null,"abstract":"<div><div>Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by spinal and cortical motor neuron loss and progressive neuromuscular decline. When ALS pathology involves the primary motor cortex (PMC), cortical excitability is often disrupted, yet how these alterations map onto motor deficits during symptomatic ALS remains unclear.</div><div>To investigate this, we examined the neuromuscular function, cortico-muscular output, and neuronal excitability of symptomatic 4-month-old TDP-43<sup>Q331K</sup> mice. TDP-43 mice exhibited reduced neuromuscular excitability and impaired strength compared to WT mice. Cranial motor evoked potentials were significantly reduced in TDP-43 mice, indicating decreased cortical output to muscle. Compared to WT mice, whole-cell patch-clamp recordings from TDP-43 PMC layer V pyramidal neurons revealed intrinsic hypoexcitability, diminished persistent inward currents (PICs), and decreased excitatory synaptic activity. Corroborating PIC findings, immunohistochemical analysis showed that PMC layer V neurons exhibited reduced signal intensity of the PIC-associated proteins Nav1.6 and 5-HT2C.</div><div>Bulk RNA-seq of the cortex showed distinct transcriptional profiles in TDP-43 mice, with enrichment analysis indicating altered pathways relating to ion transport, synaptic signaling, and neuronal excitability. These results suggest that cortex-wide transcriptional changes may reflect broader and additional molecular mechanisms underlying cortical hypoexcitability in ALS.</div><div>Together, our results demonstrate that symptomatic TDP-43<sup>Q331K</sup> mice exhibit a reduction in cortico-muscular output and PMC neuron excitability, accompanied by reduced PICs and PIC-associated proteins within these neurons. These findings identify cortical hypoexcitability as a defining feature of the TDP-43<sup>Q331k</sup> ALS mouse model and establish multi-level associations between cortical cellular-level dysfunction and impaired motor systems output.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"218 ","pages":"Article 107247"},"PeriodicalIF":5.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145843979","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-01DOI: 10.1016/j.nbd.2025.107245
Teng Teng , Shaofan Yang , Jin Li , Haoyu Wang , Fengjuan Wu , Yong He , Jihua Fan , Hongwei Shi , Mingzhu Huang , Xiang Zhou , Ying Liu , Mingyue Gong , Chuanyan Yang , Huiquan Wang , Zhenlu Cai , Hongli Li , Kuan Zhang
The astrocyte–neuron network in the primary somatosensory cortex (S1) responds dynamically to pain stimuli and plays a pivotal role in pain processing. These stimuli activate astrocytic α7-nicotinic acetylcholine receptors (α7-nAChRs), yet their contribution to pain perception remains largely unclear. This study investigates the role of astrocytic α7-nAChRs in pain information processing and perception. Astrocytic α7-nAChRs were selectively deleted by injecting rAAV5-GfaABC1D-NLS-Cre-P2A-mCherry into the S1 region of LoxP-Chrna7 transgenic mice or by tamoxifen administration in ALDH1-CreERT2:Chrna7loxP/loxP mice. Immunohistochemistry was used to assess the expression of α7-nAChR and gliotransmitter d-serine. Astrocytic Ca2+ transients were monitored in vivo using two-photon Ca2+ imaging following AAV5-GfaABC1D-cytoGCaMP6f-SV40 labeling. Neuronal Ca2+ transients in S1 evoked by plantar electric shock were recorded via fiber photometry in freely moving mice. Nociceptive and sensory behaviors were evaluated using hot plate and von Frey tests. Statistical analyses included Welch's t-tests for normally distributed data, Mann–Whitney U tests for non-normal data, and two-way ANOVA. Results showed that conditional deletion of α7-nAChRs in astrocytes markedly reduced d-serine levels within astrocytic territories. Two-photon Ca2+ imaging and fiber photometry revealed that α7-nAChR deletion attenuated both astrocytic Ca2+ transients and footshock-evoked neuronal Ca2+ activity in S1. Behaviorally, thermal pain responses were significantly impaired, whereas tactile thresholds and open-field behaviors were unaffected. These findings identify astrocytic α7-nAChRs in S1 facilitate d-serine levels and enhance astrocytic activity. Their physiological function is essential for pain-related information processing within astrocyte–neuron networks and plays a critical role in regulating pain perception.
{"title":"Astrocytic α7-nicotinic acetylcholine receptors mediate pain information processing and perception","authors":"Teng Teng , Shaofan Yang , Jin Li , Haoyu Wang , Fengjuan Wu , Yong He , Jihua Fan , Hongwei Shi , Mingzhu Huang , Xiang Zhou , Ying Liu , Mingyue Gong , Chuanyan Yang , Huiquan Wang , Zhenlu Cai , Hongli Li , Kuan Zhang","doi":"10.1016/j.nbd.2025.107245","DOIUrl":"10.1016/j.nbd.2025.107245","url":null,"abstract":"<div><div>The astrocyte–neuron network in the primary somatosensory cortex (S1) responds dynamically to pain stimuli and plays a pivotal role in pain processing. These stimuli activate astrocytic α7-nicotinic acetylcholine receptors (α7-nAChRs), yet their contribution to pain perception remains largely unclear. This study investigates the role of astrocytic α7-nAChRs in pain information processing and perception. Astrocytic α7-nAChRs were selectively deleted by injecting rAAV5-GfaABC<sub>1</sub>D-NLS-Cre-P2A-mCherry into the S1 region of LoxP-Chrna7 transgenic mice or by tamoxifen administration in ALDH1-CreERT2:Chrna7<sup>loxP/loxP</sup> mice. Immunohistochemistry was used to assess the expression of α7-nAChR and gliotransmitter <span>d</span>-serine. Astrocytic Ca<sup>2+</sup> transients were monitored in vivo using two-photon Ca<sup>2+</sup> imaging following AAV5-GfaABC<sub>1</sub>D-cytoGCaMP6f-SV40 labeling. Neuronal Ca<sup>2+</sup> transients in S1 evoked by plantar electric shock were recorded via fiber photometry in freely moving mice. Nociceptive and sensory behaviors were evaluated using hot plate and von Frey tests. Statistical analyses included Welch's <em>t</em>-tests for normally distributed data, Mann–Whitney <em>U</em> tests for non-normal data, and two-way ANOVA. Results showed that conditional deletion of α7-nAChRs in astrocytes markedly reduced <span>d</span>-serine levels within astrocytic territories. Two-photon Ca<sup>2+</sup> imaging and fiber photometry revealed that α7-nAChR deletion attenuated both astrocytic Ca<sup>2+</sup> transients and footshock-evoked neuronal Ca<sup>2+</sup> activity in S1. Behaviorally, thermal pain responses were significantly impaired, whereas tactile thresholds and open-field behaviors were unaffected. These findings identify astrocytic α7-nAChRs in S1 facilitate <span>d</span>-serine levels and enhance astrocytic activity. Their physiological function is essential for pain-related information processing within astrocyte–neuron networks and plays a critical role in regulating pain perception.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"218 ","pages":"Article 107245"},"PeriodicalIF":5.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145844000","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
APOE polymorphisms are major genetic risk factors of Alzheimer's disease (AD). Compared with APOE3/E3, the APOE4/E4 genotype is associated with a > 14-fold increased risk. Therefore, we hypothesized that conversion of APOE4 to APOE3 would ameliorate AD-related pathologies. Accordingly, we generated a knock-in mouse model harboring an APOE4-FLEx (Flip-Excision) 4-to-3 construct enabling postnatal Cre-mediated APOE4-to-APOE3 switching. This construct comprised an APOE3 exon inserted in a reverse orientation downstream of the APOE4 exon, flanked by alternating loxP and mutant loxP sites, allowing Cre-mediated FLEx switching from APOE4-to-APOE3. For in vitro validation, HEK293T cells were transfected with APOE4-FLEx 4-to-3 plasmid, followed by AAV8-mediated iCre delivery. For in vivo studies, endogenous Apoe was replaced with the APOE4-FLEx 4-to-3 construct to generate APOE4-FLEx 4-to-3 knock-in mice, which were crossed with tamoxifen-inducible Rosa26-CreERT2 mice to yield Cre: APOE4-FLEx 4-to-3 double-knock-in mice. Tamoxifen was administered to induce APOE switching. Cre expression successfully induced APOE4-to-APOE3 switching in vitro. Tamoxifen administration in Cre: APOE4-FLEx 4-to-3 mice triggered APOE4-to-APOE3 switching in the liver, demonstrating the feasibility of postnatal isoform switching. However, brain APOE protein levels were below the detection limit. Investigation of the underlying cause involving transcript analysis revealed aberrant retention of intron 3 (APOE-I3). This abnormal splicing probably contributed to the decreased expression of fully spliced, translation-competent (mature) APOE mRNA, driving the subsequent protein reduction. Although APOE expression across organs in APOE4-FLEx 4-to-3 mice requires further optimization, our findings demonstrate that Cre-mediated FLEx switching can serve as a potential strategy to induce APOE genotype switching in vivo.
{"title":"A novel conditional knock-in mouse model for APOE4-to-APOE3 switching","authors":"Ruoyi Ishikawa , Yu Yamazaki , Nayuta Nakazawa , Xin Li , Taku Tazuma , Yoshiko Takebayashi , Masahiro Nakamori , Yusuke Sotomaru , Hirofumi Maruyama","doi":"10.1016/j.nbd.2025.107244","DOIUrl":"10.1016/j.nbd.2025.107244","url":null,"abstract":"<div><div><em>APOE</em> polymorphisms are major genetic risk factors of Alzheimer's disease (AD). Compared with <em>APOE3/</em>E3, the <em>APOE4/E4</em> genotype is associated with a > 14-fold increased risk. Therefore, we hypothesized that conversion of <em>APOE4</em> to <em>APOE3</em> would ameliorate AD-related pathologies. Accordingly, we generated a knock-in mouse model harboring an APOE4-FLEx (Flip-Excision) 4-to-3 construct enabling postnatal Cre-mediated APOE4-to-APOE3 switching. This construct comprised an <em>APOE3</em> exon inserted in a reverse orientation downstream of the <em>APOE4</em> exon, flanked by alternating loxP and mutant loxP sites, allowing Cre-mediated FLEx switching from APOE4-to-APOE3. For <em>in vitro</em> validation, HEK293T cells were transfected with APOE4-FLEx 4-to-3 plasmid, followed by AAV8-mediated iCre delivery. For <em>in vivo</em> studies, endogenous <em>Apoe</em> was replaced with the APOE4-FLEx 4-to-3 construct to generate APOE4-FLEx 4-to-3 knock-in mice, which were crossed with tamoxifen-inducible Rosa26-CreERT2 mice to yield Cre: APOE4-FLEx 4-to-3 double-knock-in mice. Tamoxifen was administered to induce <em>APOE</em> switching. Cre expression successfully induced APOE4-to-APOE3 switching <em>in vitro</em>. Tamoxifen administration in Cre: APOE4-FLEx 4-to-3 mice triggered APOE4-to-APOE3 switching in the liver, demonstrating the feasibility of postnatal isoform switching. However, brain APOE protein levels were below the detection limit. Investigation of the underlying cause involving transcript analysis revealed aberrant retention of intron 3 (APOE-I3). This abnormal splicing probably contributed to the decreased expression of fully spliced, translation-competent (mature) APOE mRNA, driving the subsequent protein reduction. Although APOE expression across organs in APOE4-FLEx 4-to-3 mice requires further optimization, our findings demonstrate that Cre-mediated FLEx switching can serve as a potential strategy to induce <em>APOE</em> genotype switching <em>in vivo</em>.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"218 ","pages":"Article 107244"},"PeriodicalIF":5.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145844018","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-01DOI: 10.1016/j.nbd.2025.107135
Min Chu, Ailing Yue, Haitian Nan, Hong Ye, Miao Qu, Liyong Wu
Background
Emerging evidence implicating glymphatic dysfunction contributes to the pathogenesis of frontotemporal dementia (FTD). However, the pathway correlated to glymphatic function in FTD remains poorly understood. We aimed to explore potential underlying metabolic pathways associated with glymphatic dysfunction in FTD.
Methods
We enrolled 37 behavior FTD (bvFTD) patients and 40 healthy controls. Glymphatic activity was assessed using diffusion tensor imaging data. Plasma metabolomic profiling was performed to identify glymphatic-associated metabolites, followed by pathway enrichment analysis. Additionally, the plasma biomarker was tested in a subset of 25 patients to validate the metabolite findings.
Results
Patients with bvFTD exhibited significantly altered metabolite profiles compared to controls. The glymphatic-associated metabolites were predominantly enriched in the synaptic vesicle cycle pathway (FDR p < 0.05). Furthermore, plasma neuropentraxin-2 (NPTX2) levels positively correlated with anterior glymphatic indices (r = 0.46, p = 0.027).
Conclusion
Our findings demonstrate the association between the glymphatic system and synaptic function in bvFTD.
背景：越来越多的证据表明，淋巴功能障碍与额颞叶痴呆（FTD）的发病有关。然而，FTD中与淋巴功能相关的途径仍然知之甚少。我们的目的是探索与FTD中淋巴功能障碍相关的潜在代谢途径。方法：选取37例行为性FTD （bvFTD）患者和40例健康对照。利用弥散张量成像数据评估淋巴活性。血浆代谢组学分析鉴定淋巴相关代谢物，随后进行途径富集分析。此外，在25名患者中测试了血浆生物标志物，以验证代谢物的发现。结果：与对照组相比，bvFTD患者表现出明显改变的代谢物谱。淋巴相关代谢物主要富集于突触囊泡循环通路（FDR p ）。结论：我们的研究结果表明，bvFTD中淋巴系统与突触功能之间存在关联。
{"title":"Glymphatic activity is linked to the synaptic vesicle cycle pathway in frontotemporal dementia: A metabolomics study","authors":"Min Chu, Ailing Yue, Haitian Nan, Hong Ye, Miao Qu, Liyong Wu","doi":"10.1016/j.nbd.2025.107135","DOIUrl":"10.1016/j.nbd.2025.107135","url":null,"abstract":"<div><h3>Background</h3><div>Emerging evidence implicating glymphatic dysfunction contributes to the pathogenesis of frontotemporal dementia (FTD). However, the pathway correlated to glymphatic function in FTD remains poorly understood. We aimed to explore potential underlying metabolic pathways associated with glymphatic dysfunction in FTD.</div></div><div><h3>Methods</h3><div>We enrolled 37 behavior FTD (bvFTD) patients and 40 healthy controls. Glymphatic activity was assessed using diffusion tensor imaging data. Plasma metabolomic profiling was performed to identify glymphatic-associated metabolites, followed by pathway enrichment analysis. Additionally, the plasma biomarker was tested in a subset of 25 patients to validate the metabolite findings.</div></div><div><h3>Results</h3><div>Patients with bvFTD exhibited significantly altered metabolite profiles compared to controls. The glymphatic-associated metabolites were predominantly enriched in the synaptic vesicle cycle pathway (FDR <em>p</em> < 0.05). Furthermore, plasma neuropentraxin-2 (NPTX2) levels positively correlated with anterior glymphatic indices (<em>r</em> = 0.46, <em>p</em> = 0.027).</div></div><div><h3>Conclusion</h3><div>Our findings demonstrate the association between the glymphatic system and synaptic function in bvFTD.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"218 ","pages":"Article 107135"},"PeriodicalIF":5.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145252261","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-01DOI: 10.1016/j.nbd.2025.107231
Julia Kleniuk , Aishwarya G. Nadadhur , Catherine Rodger , Emily Wolfenden , Isabelle A. Hall , Samuel R. Cheers , Eliska Zlamalova , Evan Reid
Defective endosomal sorting and trafficking are increasingly recognised as key drivers of neurodegeneration, including hereditary spastic paraplegia (HSP) and other motor neuron disorders. Early endosomal tubule fission (ETF) is essential for sorting cargoes for recycling and retrograde transport, yet the mechanisms coordinating this process are incompletely defined. Here, we identify the endoplasmic reticulum (ER)–resident protein protrudin—previously shown to promote axonal regeneration after injury—as a key regulator of ETF. Using CRISPR interference in human cells, we show that loss of protrudin causes marked accumulation of elongated endosomal tubules, caused by defective fission. Protrudin-mediated ETF required its ability to interact with ER-localised VAP proteins, endosomal phosphoinositides, and the kinesin motor KIF5, indicating a function at ER–endosome contact sites. The endosomal tubulation phenotype depended on dynamic microtubules and dynein and was phenocopied by KIF5 depletion, suggesting that protrudin coordinates opposing microtubule motor forces to drive fission. Beyond this direct role, protrudin connects multiple ETF machineries implicated in lipid transfer, actin regulation, and ER shaping, positioning it as a central scaffold for ETF. Importantly, depletion of protrudin or the HSP-associated kinesin KIF5A produced similar endosomal tubulation defects in human cortical neurons, underscoring the neurophysiological and disease relevance of this pathway. These findings identify protrudin as a key molecular link between ER–endosome communication, neuronal membrane trafficking, and axonal maintenance—processes whose disruption underlies neurodegenerative disease.
{"title":"Protrudin acts at ER-endosome contacts to promote KIF5-mediated endosomal tubule fission","authors":"Julia Kleniuk , Aishwarya G. Nadadhur , Catherine Rodger , Emily Wolfenden , Isabelle A. Hall , Samuel R. Cheers , Eliska Zlamalova , Evan Reid","doi":"10.1016/j.nbd.2025.107231","DOIUrl":"10.1016/j.nbd.2025.107231","url":null,"abstract":"<div><div>Defective endosomal sorting and trafficking are increasingly recognised as key drivers of neurodegeneration, including hereditary spastic paraplegia (HSP) and other motor neuron disorders. Early endosomal tubule fission (ETF) is essential for sorting cargoes for recycling and retrograde transport, yet the mechanisms coordinating this process are incompletely defined. Here, we identify the endoplasmic reticulum (ER)–resident protein protrudin—previously shown to promote axonal regeneration after injury—as a key regulator of ETF. Using CRISPR interference in human cells, we show that loss of protrudin causes marked accumulation of elongated endosomal tubules, caused by defective fission. Protrudin-mediated ETF required its ability to interact with ER-localised VAP proteins, endosomal phosphoinositides, and the kinesin motor KIF5, indicating a function at ER–endosome contact sites. The endosomal tubulation phenotype depended on dynamic microtubules and dynein and was phenocopied by KIF5 depletion, suggesting that protrudin coordinates opposing microtubule motor forces to drive fission. Beyond this direct role, protrudin connects multiple ETF machineries implicated in lipid transfer, actin regulation, and ER shaping, positioning it as a central scaffold for ETF. Importantly, depletion of protrudin or the HSP-associated kinesin KIF5A produced similar endosomal tubulation defects in human cortical neurons, underscoring the neurophysiological and disease relevance of this pathway. These findings identify protrudin as a key molecular link between ER–endosome communication, neuronal membrane trafficking, and axonal maintenance—processes whose disruption underlies neurodegenerative disease.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"218 ","pages":"Article 107231"},"PeriodicalIF":5.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145810708","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Every year, 15 million babies are born preterm, putting them at increased risk of encephalopathy of prematurity (EoP). EoP is characterized by microglia-induced neuroinflammation, which can aggravate injury mechanisms leading to neuronal disorders, myelination delay, and subsequent functional consequences. While effective neuroprotective strategies in the preterm brain remain elusive, interventions such as skin-to-skin, developmental care, and music therapy have a positive impact on newborn brain development, potentially related to the oxytocinergic system. Endogenous oxytocin is recognized as a regulator of maternal-child social bonding, but its neuroprotective effect in the injured brain remains to be elucidated. Here, we investigated the effects of chemogenetic activation of oxytocinergic neurons on the neural correlates of EoP. Using a well-established mouse model of systemic interleukin-1β to induce EoP, we showed that neonatal chemogenetic activation of oxytocinergic neurons has anti-inflammatory effects in microglia, improving microstructural development of the corpus callosum and motor cortex, and rescuing typical social behavior. These neuroprotective effects were more pronounced in females, who showed a greater reduction in microgliosis and improved social behavior compared to males. This study provides a biological explanation for how developmental care and early interventions, linked to the oxytocinergic system, may induce neuroprotection in the developing brain.
{"title":"Chemogenetic activation of oxytocinergic neurons rescues neural correlates of encephalopathy of prematurity in mice","authors":"Marit Knoop , Marie-Laure Possovre , Ece Trak , Jean-Luc Pitetti , Yohan van de Looij , Eduardo Sanches , Stergios Tsartsalis , Julien Pansiot , Gabriel Schirmbeck , Olivier Baud","doi":"10.1016/j.nbd.2025.107250","DOIUrl":"10.1016/j.nbd.2025.107250","url":null,"abstract":"<div><div>Every year, 15 million babies are born preterm, putting them at increased risk of encephalopathy of prematurity (EoP). EoP is characterized by microglia-induced neuroinflammation, which can aggravate injury mechanisms leading to neuronal disorders, myelination delay, and subsequent functional consequences. While effective neuroprotective strategies in the preterm brain remain elusive, interventions such as skin-to-skin, developmental care, and music therapy have a positive impact on newborn brain development, potentially related to the oxytocinergic system. Endogenous oxytocin is recognized as a regulator of maternal-child social bonding, but its neuroprotective effect in the injured brain remains to be elucidated. Here, we investigated the effects of chemogenetic activation of oxytocinergic neurons on the neural correlates of EoP. Using a well-established mouse model of systemic interleukin-1β to induce EoP, we showed that neonatal chemogenetic activation of oxytocinergic neurons has anti-inflammatory effects in microglia, improving microstructural development of the corpus callosum and motor cortex, and rescuing typical social behavior. These neuroprotective effects were more pronounced in females, who showed a greater reduction in microgliosis and improved social behavior compared to males. This study provides a biological explanation for how developmental care and early interventions, linked to the oxytocinergic system, may induce neuroprotection in the developing brain.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"218 ","pages":"Article 107250"},"PeriodicalIF":5.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145850454","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Retraction Notice to “Hypercholesterolemia-induced A<beta> accumulation in rabbit brain is associated with alteration in IGF-1 signaling” [Neurobiology of Disease 32 (2008) 426–432]","authors":"Sunita Sharma, R.P. Jaya Prasanthi, Eric Schommer, Gwen Feist, Othman Ghribi","doi":"10.1016/j.nbd.2025.107204","DOIUrl":"10.1016/j.nbd.2025.107204","url":null,"abstract":"","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"218 ","pages":"Article 107204"},"PeriodicalIF":5.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145669071","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-01DOI: 10.1016/j.nbd.2025.107240
Anabel M.M. Miguelez Fernández, Shana Netherton, Seshadri B. Niladhuri, Alexander C. Brown, Patricia Rivera, Kuei Y. Tseng, Christian J. Peters
Chronic exposure to nicotine results in the development of a dependent state such that a withdrawal syndrome is elicited upon cessation of nicotine. The interpeduncular nucleus (IPN) contains a high concentration of nicotinic acetylcholine receptors (nAChRs) and has been identified as a key brain region involved in nicotine withdrawal. Here we investigated the contribution of two distinct subpopulations of IPN GABAergic neurons to nicotine withdrawal behaviors. Withdrawal was induced in mice by implantation of osmotic pumps containing nicotine, followed by precipitation by intraperitoneal injections of mecamylamine. Using a chemogenetic approach to specifically target Amigo1-expressing or Epyc-expressing neurons within the IPN, we found that activity of the Amigo1 subpopulation of GABAergic neurons is critical for anxiety-like behaviors both in naïve mice and in those undergoing nicotine withdrawal. Moreover, data revealed that stimulation of Amigo1 neurons in nicotine-naïve mice elicits opposite effects on affective and somatic behaviors. Taken together, these results suggest that somatic and affective behaviors constitute dissociable components of the nicotine withdrawal phenotype and are likely supported by distinct subpopulations of neurons within the IPN.
{"title":"Chemogenetic control of GABAergic neurons within the interpeduncular nucleus reveals dissociable behavioral components of the nicotine withdrawal phenotype","authors":"Anabel M.M. Miguelez Fernández, Shana Netherton, Seshadri B. Niladhuri, Alexander C. Brown, Patricia Rivera, Kuei Y. Tseng, Christian J. Peters","doi":"10.1016/j.nbd.2025.107240","DOIUrl":"10.1016/j.nbd.2025.107240","url":null,"abstract":"<div><div>Chronic exposure to nicotine results in the development of a dependent state such that a withdrawal syndrome is elicited upon cessation of nicotine. The interpeduncular nucleus (IPN) contains a high concentration of nicotinic acetylcholine receptors (nAChRs) and has been identified as a key brain region involved in nicotine withdrawal. Here we investigated the contribution of two distinct subpopulations of IPN GABAergic neurons to nicotine withdrawal behaviors. Withdrawal was induced in mice by implantation of osmotic pumps containing nicotine, followed by precipitation by intraperitoneal injections of mecamylamine. Using a chemogenetic approach to specifically target Amigo1-expressing or Epyc-expressing neurons within the IPN, we found that activity of the Amigo1 subpopulation of GABAergic neurons is critical for anxiety-like behaviors both in naïve mice and in those undergoing nicotine withdrawal. Moreover, data revealed that stimulation of Amigo1 neurons in nicotine-naïve mice elicits opposite effects on affective and somatic behaviors. Taken together, these results suggest that somatic and affective behaviors constitute dissociable components of the nicotine withdrawal phenotype and are likely supported by distinct subpopulations of neurons within the IPN.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"218 ","pages":"Article 107240"},"PeriodicalIF":5.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145827989","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-01DOI: 10.1016/j.nbd.2025.107248
Ruting Fu , Liya Fang , Jiahao Liu , Yuanyuan Liu , Yeyan Wang , Deming Kong , Jin Guo
Although targeting neuronal excitability remains the cornerstone of epilepsy treatment, the high prevalence of drug-resistant epilepsy compels a reexamination of its upstream mechanisms. Growing evidence identifies redox imbalance and specific cell death programs as key drivers of epileptogenesis. We propose a unified framework. Here, we position dysfunction of mitochondria-associated endoplasmic reticulum membranes (MAMs) linked to ferroptosis as a core pathogenic axis. Multiple epileptogenic triggers converge to pathologically remodel MAMs, transforming them into a catalytic platform that efficiently initiates ferroptosis. This is achieved through the nanoscale co-localization of calcium ions, reactive oxygen species, and unstable iron. We systematically dissect how MAMs integrate calcium signaling, lipid metabolism, and redox balance, and outline core ferroptosis pathways. Critically, MAMs remodeling subverts antioxidant defenses, reprograms lipid metabolism, and irreversibly drives ferroptosis. This MAMs-ferroptosis axis promotes epilepsy chronicity by mediating selective neuronal loss, amplifying neuroinflammation, and disrupting excitatory-inhibitory balance. Based on this mechanism, we propose a novel therapeutic paradigm: stabilizing MAMs upstream with Sigma-1 receptor ligands, combined with neutralizing lipid peroxides downstream using ferroptosis inhibitors. This multi-tiered strategy provides a foundation for developing disease-modifying, next-generation epilepsy therapies.
{"title":"Mitochondrial-associated endoplasmic reticulum membranes (MAMs) drive ferroptosis via redox signaling: A key potential mechanism in epilepsy","authors":"Ruting Fu , Liya Fang , Jiahao Liu , Yuanyuan Liu , Yeyan Wang , Deming Kong , Jin Guo","doi":"10.1016/j.nbd.2025.107248","DOIUrl":"10.1016/j.nbd.2025.107248","url":null,"abstract":"<div><div>Although targeting neuronal excitability remains the cornerstone of epilepsy treatment, the high prevalence of drug-resistant epilepsy compels a reexamination of its upstream mechanisms. Growing evidence identifies redox imbalance and specific cell death programs as key drivers of epileptogenesis. We propose a unified framework. Here, we position dysfunction of mitochondria-associated endoplasmic reticulum membranes (MAMs) linked to ferroptosis as a core pathogenic axis. Multiple epileptogenic triggers converge to pathologically remodel MAMs, transforming them into a catalytic platform that efficiently initiates ferroptosis. This is achieved through the nanoscale co-localization of calcium ions, reactive oxygen species, and unstable iron. We systematically dissect how MAMs integrate calcium signaling, lipid metabolism, and redox balance, and outline core ferroptosis pathways. Critically, MAMs remodeling subverts antioxidant defenses, reprograms lipid metabolism, and irreversibly drives ferroptosis. This MAMs-ferroptosis axis promotes epilepsy chronicity by mediating selective neuronal loss, amplifying neuroinflammation, and disrupting excitatory-inhibitory balance. Based on this mechanism, we propose a novel therapeutic paradigm: stabilizing MAMs upstream with Sigma-1 receptor ligands, combined with neutralizing lipid peroxides downstream using ferroptosis inhibitors. This multi-tiered strategy provides a foundation for developing disease-modifying, next-generation epilepsy therapies.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"218 ","pages":"Article 107248"},"PeriodicalIF":5.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145846682","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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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