Generating functional maturation neural organoids to model degenerative disease or replace large damaged central nervous tissue remains an enormous challenge. Here, we developed a novel blood vessel-mimicking nanomaterial system by combining carboxylated cellulose nanofibers (CCN) with Matrigel to create biosafety scaffolds. These engineered scaffolds demonstrated a remarkable capacity to support the long-term growth over 300 days and functional maturation of neural organoids, enabling the development of centimeter-scale organoids without necrotic cores. CCN-engineered human spinal cord organoids (ChSOs) could self-elongate axon tracts, robustly form axon myelination and establish functional neural networks. Following transplantation, ChSOs demonstrated remarkable differentiation potential, generating both dorsal and ventral multiple subtype spinal cord neurons, which could migrate and sufficiently integrate with the host spinal cord tissue. Notably, these grafted ChSOs highly secrete axon guidance factor NTN1 enhancing axonogenesis and facilitate the restoration of sensory and motor functions of complete SCI in mice. These findings show that ChSOs offer a platform to study neural development and achieve functional spinal cord repair.
{"title":"Transplantation of engineered spinal cord organoids restores functions after spinal cord injury.","authors":"Linlin Liu,Weiwei Xue,Yufei Kong,Huijuan Li,Qi Fan,Jingyi Shi,Huihui Liu,Jinhong Xu,Yujie Xiao,Hongli Wang,Bo Li,Shengxi Wu,Zhicheng Shao","doi":"10.1093/brain/awaf471","DOIUrl":"https://doi.org/10.1093/brain/awaf471","url":null,"abstract":"Generating functional maturation neural organoids to model degenerative disease or replace large damaged central nervous tissue remains an enormous challenge. Here, we developed a novel blood vessel-mimicking nanomaterial system by combining carboxylated cellulose nanofibers (CCN) with Matrigel to create biosafety scaffolds. These engineered scaffolds demonstrated a remarkable capacity to support the long-term growth over 300 days and functional maturation of neural organoids, enabling the development of centimeter-scale organoids without necrotic cores. CCN-engineered human spinal cord organoids (ChSOs) could self-elongate axon tracts, robustly form axon myelination and establish functional neural networks. Following transplantation, ChSOs demonstrated remarkable differentiation potential, generating both dorsal and ventral multiple subtype spinal cord neurons, which could migrate and sufficiently integrate with the host spinal cord tissue. Notably, these grafted ChSOs highly secrete axon guidance factor NTN1 enhancing axonogenesis and facilitate the restoration of sensory and motor functions of complete SCI in mice. These findings show that ChSOs offer a platform to study neural development and achieve functional spinal cord repair.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"1 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145777443","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}
Anna Steward,Anna Dewenter,Fabian Hirsch,Sebastian N Roemer-Cassiano,Zeyu Zhu,Amir Dehsarvi,Davina Biel,Madleen Klonowski,Lukas Frontzkowski,Carla Palleis,Johannes Gnörich,Martin Dichgans,Günter Höglinger,Matthias Brendel,Nicolai Franzmeier
In Alzheimer's disease, carriage of the ApoE4 risk allele is linked to faster tau accumulation at lower amyloid-PET levels, thereby accelerating disease progression. However, it remains unclear whether this ApoE4-facilitated transition from amyloidosis to tauopathy is mechanistically promoted by increased secretion of phosphorylated (p)tau, a key intermediate that drives the amyloid-to-tauopathy transition, or alternatively by increased ptau-driven tau aggregation. Therefore, we investigated where along the amyloid-to-tau axis ApoE4 accelerates tau aggregation and assessed i) whether ApoE4 increases ptau secretion or ii) whether ApoE4 increases ptau-associated tau aggregation. To this end, we analysed two large-scale APOE-genotyped cohorts covering the full Alzheimer's disease spectrum (ADNI: n=201) as well as a preclinical cohort (A4-LEARN: n=200), integrating baseline amyloid-PET, plasma ptau217 and CSF ptau181 with longitudinal tau-PET. Using linear regression, we tested whether ApoE4-carriage moderates i) amyloid-PET-associated plasma ptau217 increases or ii) ptau217-associated tau spreading from local epicentres across patient-tailored tau spreading stages. All analyses were independently validated across both cohorts, including an additional replication in an ADNI subset (n=115) with available CSF ptau181 measures as an alternative marker of ptau secretion. Finally, we used logistic regression to determine ApoE4 allele count-stratified plasma ptau217 thresholds marking early pathological tau-PET increases. We found that ApoE4 did not facilitate amyloid-PET-associated ptau increases, suggesting that amyloid-related ptau secretion is not altered by ApoE4-carriage. Contrastingly, we found that plasma ptau217 elevations were linked to faster tau-PET spread from local epicentres across connected brain regions in an ApoE4-allele dose-dependent manner, independent of amyloid (ADNI/A4-LEARN: mean β=0.44/0.56, p<0.001/<0.001). Lastly, we found that a higher ApoE4 allele count was linked to lower ptau217 thresholds marking transition to tauopathy, i.e. early abnormal tau-PET increases, consistently across both samples (ADNI: 0/1/2 ApoE4 alleles=0.62/0.34/0.15pg/ml, representing ∼45% and ∼76% reductions from non-carriers; Fujirebio ptau217 assay; A4/LEARN: 0/1/2 ApoE4 alleles=0.31/0.23/0.18pg/ml, representing ∼26% and ∼42% reductions; Eli Lilly ptau217 assay). These findings suggest that ApoE4, i.e. the key genetic risk factor for sporadic Alzheimer's disease, facilitates amyloid-dependent tau aggregation in an allele dose-dependent manner by enhancing the ptau-driven spread of fibrillar tau, leading to an earlier transition from amyloidosis to tauopathy at lower ptau217 levels. This has implications for plasma ptau-based screening approaches and therapeutic timing of anti-amyloid drugs in ApoE4 carriers: Specifically, ApoE4 carriers may require genotype-adjusted ptau thresholds to detect Alzheimer's disease pathophysiology, as well as anti-amyloid tr
{"title":"ApoE4 lowers the ptau217 threshold for tau aggregation and spread in an allele dose-dependent manner.","authors":"Anna Steward,Anna Dewenter,Fabian Hirsch,Sebastian N Roemer-Cassiano,Zeyu Zhu,Amir Dehsarvi,Davina Biel,Madleen Klonowski,Lukas Frontzkowski,Carla Palleis,Johannes Gnörich,Martin Dichgans,Günter Höglinger,Matthias Brendel,Nicolai Franzmeier","doi":"10.1093/brain/awaf463","DOIUrl":"https://doi.org/10.1093/brain/awaf463","url":null,"abstract":"In Alzheimer's disease, carriage of the ApoE4 risk allele is linked to faster tau accumulation at lower amyloid-PET levels, thereby accelerating disease progression. However, it remains unclear whether this ApoE4-facilitated transition from amyloidosis to tauopathy is mechanistically promoted by increased secretion of phosphorylated (p)tau, a key intermediate that drives the amyloid-to-tauopathy transition, or alternatively by increased ptau-driven tau aggregation. Therefore, we investigated where along the amyloid-to-tau axis ApoE4 accelerates tau aggregation and assessed i) whether ApoE4 increases ptau secretion or ii) whether ApoE4 increases ptau-associated tau aggregation. To this end, we analysed two large-scale APOE-genotyped cohorts covering the full Alzheimer's disease spectrum (ADNI: n=201) as well as a preclinical cohort (A4-LEARN: n=200), integrating baseline amyloid-PET, plasma ptau217 and CSF ptau181 with longitudinal tau-PET. Using linear regression, we tested whether ApoE4-carriage moderates i) amyloid-PET-associated plasma ptau217 increases or ii) ptau217-associated tau spreading from local epicentres across patient-tailored tau spreading stages. All analyses were independently validated across both cohorts, including an additional replication in an ADNI subset (n=115) with available CSF ptau181 measures as an alternative marker of ptau secretion. Finally, we used logistic regression to determine ApoE4 allele count-stratified plasma ptau217 thresholds marking early pathological tau-PET increases. We found that ApoE4 did not facilitate amyloid-PET-associated ptau increases, suggesting that amyloid-related ptau secretion is not altered by ApoE4-carriage. Contrastingly, we found that plasma ptau217 elevations were linked to faster tau-PET spread from local epicentres across connected brain regions in an ApoE4-allele dose-dependent manner, independent of amyloid (ADNI/A4-LEARN: mean β=0.44/0.56, p<0.001/<0.001). Lastly, we found that a higher ApoE4 allele count was linked to lower ptau217 thresholds marking transition to tauopathy, i.e. early abnormal tau-PET increases, consistently across both samples (ADNI: 0/1/2 ApoE4 alleles=0.62/0.34/0.15pg/ml, representing ∼45% and ∼76% reductions from non-carriers; Fujirebio ptau217 assay; A4/LEARN: 0/1/2 ApoE4 alleles=0.31/0.23/0.18pg/ml, representing ∼26% and ∼42% reductions; Eli Lilly ptau217 assay). These findings suggest that ApoE4, i.e. the key genetic risk factor for sporadic Alzheimer's disease, facilitates amyloid-dependent tau aggregation in an allele dose-dependent manner by enhancing the ptau-driven spread of fibrillar tau, leading to an earlier transition from amyloidosis to tauopathy at lower ptau217 levels. This has implications for plasma ptau-based screening approaches and therapeutic timing of anti-amyloid drugs in ApoE4 carriers: Specifically, ApoE4 carriers may require genotype-adjusted ptau thresholds to detect Alzheimer's disease pathophysiology, as well as anti-amyloid tr","PeriodicalId":9063,"journal":{"name":"Brain","volume":"47 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145771569","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}
Luisa Weiss, Macarena Pavez, Anastasia Labudina, Liliia Andriichuk, Owen Jones, Amy Jones, Deanna Barwick, Zandra Jenkins, Indranil Basak, Tim Morgan, Teresa Neuhann, Julia Rankin, Jacques Giltay, Emanuele Agolini, Antonio Novelli, Antonio Pizzuti, Daniel C Koboldt, Swetha Ramadesikan, Leeran B Dublin-Ryan, Stephanie Hughes, Nataylia Di Donato, Greg Gimenez, Takashi Namba, Laura F Gumy, Stephen P Robertson
The establishment of neuronal polarity, whereby somatodendritic and axonal cellular compartments are defined, is a critical determinant for the development of neuronal networks and patterning during neurogenesis. The axon initial segment (AIS), a key structure in the establishment of this polarity, is formed through interactions between the microtubule and actin cytoskeleton, Ankyrin G, TRIM46 and multiple transmembrane and perimembranous proteins. Here we implicate a component of the septin cytoskeleton, Septin-2, in the maintenance and function of the AIS through the study of mutations found in five unrelated human individuals and one mother-daughter duo with a majority presenting with cognitive impairment. Septins form octameric rods that assemble into higher order filamentous scaffolds driven by Septin-2 homodimerization. Mutant Septin-2 is predicted to impart a dominant negative blockade on septin octamers forming these structures by precluding Septin-2 homodimerization. Expression of mutant Septin-2 constructs in neurons leads to the disappearance of canonical hallmarks of the AIS. This includes loss of Ankyrin G in the AIS, aberrant localization of MAP2 within the distal axon, axonal shortening and electrophysiological hypoexcitability. We further show that Septin-2 binds to a neuron-specific domain of Ankyrin G, an interaction that is largely ablated by these mutations. These data establish a role for Septin-2 in the maintenance and function of the AIS and implicate cytoskeletal structures composed of septin oligomers in the establishment of higher cognitive functions in humans.
{"title":"A functional role for septin-2 in the maintenance of the axon initial segment and in human cognitive development","authors":"Luisa Weiss, Macarena Pavez, Anastasia Labudina, Liliia Andriichuk, Owen Jones, Amy Jones, Deanna Barwick, Zandra Jenkins, Indranil Basak, Tim Morgan, Teresa Neuhann, Julia Rankin, Jacques Giltay, Emanuele Agolini, Antonio Novelli, Antonio Pizzuti, Daniel C Koboldt, Swetha Ramadesikan, Leeran B Dublin-Ryan, Stephanie Hughes, Nataylia Di Donato, Greg Gimenez, Takashi Namba, Laura F Gumy, Stephen P Robertson","doi":"10.1093/brain/awaf468","DOIUrl":"https://doi.org/10.1093/brain/awaf468","url":null,"abstract":"The establishment of neuronal polarity, whereby somatodendritic and axonal cellular compartments are defined, is a critical determinant for the development of neuronal networks and patterning during neurogenesis. The axon initial segment (AIS), a key structure in the establishment of this polarity, is formed through interactions between the microtubule and actin cytoskeleton, Ankyrin G, TRIM46 and multiple transmembrane and perimembranous proteins. Here we implicate a component of the septin cytoskeleton, Septin-2, in the maintenance and function of the AIS through the study of mutations found in five unrelated human individuals and one mother-daughter duo with a majority presenting with cognitive impairment. Septins form octameric rods that assemble into higher order filamentous scaffolds driven by Septin-2 homodimerization. Mutant Septin-2 is predicted to impart a dominant negative blockade on septin octamers forming these structures by precluding Septin-2 homodimerization. Expression of mutant Septin-2 constructs in neurons leads to the disappearance of canonical hallmarks of the AIS. This includes loss of Ankyrin G in the AIS, aberrant localization of MAP2 within the distal axon, axonal shortening and electrophysiological hypoexcitability. We further show that Septin-2 binds to a neuron-specific domain of Ankyrin G, an interaction that is largely ablated by these mutations. These data establish a role for Septin-2 in the maintenance and function of the AIS and implicate cytoskeletal structures composed of septin oligomers in the establishment of higher cognitive functions in humans.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"57 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145770709","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}
Erika A Aguzzi, Roshni A Desai, Zhiyuan Yang, Andrew L Davies, Don Mahad, Bernard Siow, Ayse G Yenicelik, Radha Desai, Eleni Giama, AlBeshr Almasri, Miranda Colman, Celine Geywitz, Lucas Schirmer, Paul A Felts, Kenneth J Smith
Acutely inflamed CNS lesions can be sufficiently hypoxic to cause temporary neurological disability. A new experimental lesion reveals that brief hypoxia can also ignite a slow-burning atrophy of the grey matter, resulting in a lifetime of slowly progressive disability. The progressive disability eventually exceeds that observed acutely, indicating that acutely functioning tissue can nevertheless be destined to atrophy. Remarkably, both the temporary initial disability and the ensuing progressive disability and atrophy are significantly reduced if the acute hypoxia is avoided by four days of treatment with vasodilating nimodipine, or by simply breathing raised oxygen concentration. Thus, a lifetime of progressive disability and neurodegeneration can be the legacy of a few days of inflammatory hypoxia experienced in young adulthood, and avoided by maintaining lesion oxygenation. The findings may help to understand and treat some progressive neurological disorders, including multiple sclerosis.
{"title":"A cause and protective treatment for acute and progressive disability and grey matter atrophy","authors":"Erika A Aguzzi, Roshni A Desai, Zhiyuan Yang, Andrew L Davies, Don Mahad, Bernard Siow, Ayse G Yenicelik, Radha Desai, Eleni Giama, AlBeshr Almasri, Miranda Colman, Celine Geywitz, Lucas Schirmer, Paul A Felts, Kenneth J Smith","doi":"10.1093/brain/awaf465","DOIUrl":"https://doi.org/10.1093/brain/awaf465","url":null,"abstract":"Acutely inflamed CNS lesions can be sufficiently hypoxic to cause temporary neurological disability. A new experimental lesion reveals that brief hypoxia can also ignite a slow-burning atrophy of the grey matter, resulting in a lifetime of slowly progressive disability. The progressive disability eventually exceeds that observed acutely, indicating that acutely functioning tissue can nevertheless be destined to atrophy. Remarkably, both the temporary initial disability and the ensuing progressive disability and atrophy are significantly reduced if the acute hypoxia is avoided by four days of treatment with vasodilating nimodipine, or by simply breathing raised oxygen concentration. Thus, a lifetime of progressive disability and neurodegeneration can be the legacy of a few days of inflammatory hypoxia experienced in young adulthood, and avoided by maintaining lesion oxygenation. The findings may help to understand and treat some progressive neurological disorders, including multiple sclerosis.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"76 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145759442","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}
Daryl Lawrence, Guy Avraham, Jiaang Yao, Lexin Li, Chengchun Shi, Philip A Starr, Simon J Little
The basal ganglia and sensorimotor cortex are essential nodes of a network that supports motor control. In Parkinson’s disease, disruptions in this network lead to rigidity and slowness during movement execution. Deep brain stimulation (DBS) of the basal ganglia has proven effective in alleviating Parkinson’s disease-related hypokinetic symptoms, and sensing-enabled neurostimulators now afford the opportunity to detect cortico-basal oscillations during motion. However, the specific contributions of these motor network nodes to chronic, naturalistic movement and the effects of DBS on circuit dynamics are not well understood. To address these gaps, we recorded over 530 hours of cortical and subcortical signals from 15 Parkinson’s disease patients (27 hemispheres) during unsupervised, unconstrained daily activities and subthalamic or pallidal DBS. Synchronized wrist-worn accelerometers tracked forearm speeds, supporting the evaluation of neural biomarkers related to motion. Our study validated and extended the known relationship between cortical and subcortical beta power (13–30 Hz) and movement. We show that cortical low (13–20 Hz) and high (21–30 Hz) beta movement-related desynchronization (MRD) effectively distinguished between mobile and stationary states. In the subthalamic nucleus (STN) and globus pallidus interna (GPi), high beta MRD and gamma (40–80 Hz) movement-related synchronization (MRS) exhibited significant group-level correlations with movement kinematics. When stimulated at 130 Hz, cortical stimulation-entrained gamma oscillations at the half-harmonic (∼65 Hz) were observed. Further, cortical entrained gamma MRS was a stronger predictor of motion than broadband gamma MRS. We developed machine learning (ML) models to predict naturalistic movement over extended periods using spectral features from brief neural recordings (0.5–8 s epochs). Cortical models outperformed subcortical models, although combining cortico-basal signals yielded the highest model performance (AUC > 0.85 for binary movement state classifiers; Pearson r statistic > 0.68 for continuous forearm speed regressors). Higher DBS current amplitudes were associated with reduced beta MRD and low gamma (40–60 Hz) MRS in the STN/GPi. This negatively impacted the accuracy of the subcortical models, whereas cortical and cortico-basal model performance remained stable across stimulation amplitudes. Our study demonstrates that cortico-basal nodes of the motor network encode complementary kinematic information, which can be integrated to enhance the accuracy and stability of chronic, naturalistic movement decoding during deep brain stimulation. These insights support the development and integration of therapeutic brain-computer interfaces (BCIs) with closed-loop, adaptive DBS (aDBS) to leverage rapid and precise movement-predictive models for the treatment of motor network disorders.
{"title":"Cortico-basal oscillations index naturalistic movements during deep brain stimulation","authors":"Daryl Lawrence, Guy Avraham, Jiaang Yao, Lexin Li, Chengchun Shi, Philip A Starr, Simon J Little","doi":"10.1093/brain/awaf466","DOIUrl":"https://doi.org/10.1093/brain/awaf466","url":null,"abstract":"The basal ganglia and sensorimotor cortex are essential nodes of a network that supports motor control. In Parkinson’s disease, disruptions in this network lead to rigidity and slowness during movement execution. Deep brain stimulation (DBS) of the basal ganglia has proven effective in alleviating Parkinson’s disease-related hypokinetic symptoms, and sensing-enabled neurostimulators now afford the opportunity to detect cortico-basal oscillations during motion. However, the specific contributions of these motor network nodes to chronic, naturalistic movement and the effects of DBS on circuit dynamics are not well understood. To address these gaps, we recorded over 530 hours of cortical and subcortical signals from 15 Parkinson’s disease patients (27 hemispheres) during unsupervised, unconstrained daily activities and subthalamic or pallidal DBS. Synchronized wrist-worn accelerometers tracked forearm speeds, supporting the evaluation of neural biomarkers related to motion. Our study validated and extended the known relationship between cortical and subcortical beta power (13–30 Hz) and movement. We show that cortical low (13–20 Hz) and high (21–30 Hz) beta movement-related desynchronization (MRD) effectively distinguished between mobile and stationary states. In the subthalamic nucleus (STN) and globus pallidus interna (GPi), high beta MRD and gamma (40–80 Hz) movement-related synchronization (MRS) exhibited significant group-level correlations with movement kinematics. When stimulated at 130 Hz, cortical stimulation-entrained gamma oscillations at the half-harmonic (∼65 Hz) were observed. Further, cortical entrained gamma MRS was a stronger predictor of motion than broadband gamma MRS. We developed machine learning (ML) models to predict naturalistic movement over extended periods using spectral features from brief neural recordings (0.5–8 s epochs). Cortical models outperformed subcortical models, although combining cortico-basal signals yielded the highest model performance (AUC &gt; 0.85 for binary movement state classifiers; Pearson r statistic &gt; 0.68 for continuous forearm speed regressors). Higher DBS current amplitudes were associated with reduced beta MRD and low gamma (40–60 Hz) MRS in the STN/GPi. This negatively impacted the accuracy of the subcortical models, whereas cortical and cortico-basal model performance remained stable across stimulation amplitudes. Our study demonstrates that cortico-basal nodes of the motor network encode complementary kinematic information, which can be integrated to enhance the accuracy and stability of chronic, naturalistic movement decoding during deep brain stimulation. These insights support the development and integration of therapeutic brain-computer interfaces (BCIs) with closed-loop, adaptive DBS (aDBS) to leverage rapid and precise movement-predictive models for the treatment of motor network disorders.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"13 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145760073","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}
Juan Zu, Cong Li, Mochen Cui, Xinwu Liu, Zhouyang Pan, Xiaohe Li, Fang Zhang, Johanna Gentz, Gerda Mitteregger-Kretzschmar, Jochen Herms, Yuan Shi
Synaptic loss is an early hallmark of Alzheimer’s disease (AD), predominantly driven by aberrant microglial reactivity. Pioglitazone, a peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist with anti-diabetic properties, has been shown to suppress microglial activity and improve cognitive performance in both AD models and clinical studies. However, whether its neuroprotective effects involve direct modulation of synaptic architecture remains unclear. Here, using longitudinal in vivo two-photon imaging, multi-channel immunohistochemistry, super-resolution confocal microscopy, and 3D reconstruction techniques in an AD mouse model, we analysed synaptic and microglial interactions. We show that a 4-week pioglitazone treatment preserves dendritic spine density and enhances spine stability over time. Mechanistically, pioglitazone reduces synaptic C1q deposition, thereby limiting complement-mediated microglial synaptic engulfment and attenuating synapse loss. These findings identify pioglitazone as a modulator of complement-dependent microglial synaptic pruning and support its therapeutic potential in preserving synaptic integrity during early AD pathogenesis.
{"title":"Pioglitazone attenuates complement-mediated microglial synaptic engulfment in an Alzheimer’s disease model","authors":"Juan Zu, Cong Li, Mochen Cui, Xinwu Liu, Zhouyang Pan, Xiaohe Li, Fang Zhang, Johanna Gentz, Gerda Mitteregger-Kretzschmar, Jochen Herms, Yuan Shi","doi":"10.1093/brain/awaf462","DOIUrl":"https://doi.org/10.1093/brain/awaf462","url":null,"abstract":"Synaptic loss is an early hallmark of Alzheimer’s disease (AD), predominantly driven by aberrant microglial reactivity. Pioglitazone, a peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist with anti-diabetic properties, has been shown to suppress microglial activity and improve cognitive performance in both AD models and clinical studies. However, whether its neuroprotective effects involve direct modulation of synaptic architecture remains unclear. Here, using longitudinal in vivo two-photon imaging, multi-channel immunohistochemistry, super-resolution confocal microscopy, and 3D reconstruction techniques in an AD mouse model, we analysed synaptic and microglial interactions. We show that a 4-week pioglitazone treatment preserves dendritic spine density and enhances spine stability over time. Mechanistically, pioglitazone reduces synaptic C1q deposition, thereby limiting complement-mediated microglial synaptic engulfment and attenuating synapse loss. These findings identify pioglitazone as a modulator of complement-dependent microglial synaptic pruning and support its therapeutic potential in preserving synaptic integrity during early AD pathogenesis.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"12 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145759444","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}
Thomas G Simpson, Shenghong He, Laura Wehmeyer, Alek Pogosyan, Fernando Rodriguez Plazas, Ashwini Oswal, Michael G Hart, Rahul S Shah, Harutomo Hasegawa, Christoph Wiest, Sahar Yassine, Xuanjun Guo, Philipp A Loehrer, Anca Merla, Pablo Andrade, Veerle Visser-Vandewalle, Andrea Perera, Kenneth Adindu, Ahmed Raslan, Andrew O’Keeffe, Marie-Laure Welter, Francesca Morgante, Keyoumars Ashkan, Erlick A Pereira, Huiling Tan
Freezing of gait (FOG) is a devastating symptom of Parkinson’s disease (PD) often resulting in disabling falls and loss of independence. It affects half of patients, yet current therapeutic strategies are insufficient, and the underlying neural mechanisms remain poorly understood. This study investigated beta oscillation dynamics in the subthalamic nucleus (STN) during different movement states (sitting, standing, and stepping), while examining the effects of levodopa. Specifically, it aimed to identify pathological activity during stepping by analysing the relationship between the STN and leg muscles and how this is modulated by levodopa. Local field potentials (LFP) in the STN and leg muscle activity measured as Electromyography (EMG) of the gastrocnemius and peroneus longus were recorded in 14 PD patients during sitting, standing, and stepping, ON and OFF levodopa. Levodopa reduced stepping frequency variability, implying improved stepping rhythmicity. Low-beta (12-20 Hz) and high-beta (21-35 Hz) were differentially modulated by stepping movements and levodopa, with reduced high-beta and increased low-beta during stepping compared to standing and sitting. In contrast, levodopa reduced low-beta but increased high-beta activity, highlighting a potential physiological function of high-beta in the STN. Additionally, step-phase specific effects of levodopa were observed including reduced broad-beta band activity in the STN and leg muscles during the late stance and lift-off phase of the contralateral leg when ON medication. Furthermore, STN beta bursts were associated with increased muscle activation at movement initiation, potentially reducing the ability to move freely. This study observed different effects of movement status (sitting vs. stepping vs. standing) on the average amplitude of low- versus high-beta frequency bands, suggesting they may serve distinct functional roles. Furthermore, there is a step-phase specific effect of levodopa on STN LFPs, EMGs, and intermuscular coherence during stepping. These findings offer insight for developing phase-specific stimulation strategies targeting STN beta oscillations during gait.
{"title":"Dopamine and the dynamics of subthalamic and leg muscle activities in parkinsonian stepping","authors":"Thomas G Simpson, Shenghong He, Laura Wehmeyer, Alek Pogosyan, Fernando Rodriguez Plazas, Ashwini Oswal, Michael G Hart, Rahul S Shah, Harutomo Hasegawa, Christoph Wiest, Sahar Yassine, Xuanjun Guo, Philipp A Loehrer, Anca Merla, Pablo Andrade, Veerle Visser-Vandewalle, Andrea Perera, Kenneth Adindu, Ahmed Raslan, Andrew O’Keeffe, Marie-Laure Welter, Francesca Morgante, Keyoumars Ashkan, Erlick A Pereira, Huiling Tan","doi":"10.1093/brain/awaf464","DOIUrl":"https://doi.org/10.1093/brain/awaf464","url":null,"abstract":"Freezing of gait (FOG) is a devastating symptom of Parkinson’s disease (PD) often resulting in disabling falls and loss of independence. It affects half of patients, yet current therapeutic strategies are insufficient, and the underlying neural mechanisms remain poorly understood. This study investigated beta oscillation dynamics in the subthalamic nucleus (STN) during different movement states (sitting, standing, and stepping), while examining the effects of levodopa. Specifically, it aimed to identify pathological activity during stepping by analysing the relationship between the STN and leg muscles and how this is modulated by levodopa. Local field potentials (LFP) in the STN and leg muscle activity measured as Electromyography (EMG) of the gastrocnemius and peroneus longus were recorded in 14 PD patients during sitting, standing, and stepping, ON and OFF levodopa. Levodopa reduced stepping frequency variability, implying improved stepping rhythmicity. Low-beta (12-20 Hz) and high-beta (21-35 Hz) were differentially modulated by stepping movements and levodopa, with reduced high-beta and increased low-beta during stepping compared to standing and sitting. In contrast, levodopa reduced low-beta but increased high-beta activity, highlighting a potential physiological function of high-beta in the STN. Additionally, step-phase specific effects of levodopa were observed including reduced broad-beta band activity in the STN and leg muscles during the late stance and lift-off phase of the contralateral leg when ON medication. Furthermore, STN beta bursts were associated with increased muscle activation at movement initiation, potentially reducing the ability to move freely. This study observed different effects of movement status (sitting vs. stepping vs. standing) on the average amplitude of low- versus high-beta frequency bands, suggesting they may serve distinct functional roles. Furthermore, there is a step-phase specific effect of levodopa on STN LFPs, EMGs, and intermuscular coherence during stepping. These findings offer insight for developing phase-specific stimulation strategies targeting STN beta oscillations during gait.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"145 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145731090","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}
Shruti Agrawal, Rebekah Mannix, Vicki Anderson, Miriam Beauchamp, Adam Ferguson, Lucia W Braga, Shu-Ling Chong, Anthony Figaji, Christopher Giza, David K Menon, Michael J Bell
Paediatric traumatic brain injury (pTBI) remains a leading cause of death and disability in children around the world. The evidence to support pTBI management in children notably lags that in adult populations with a lack of data available to inform management. Injury mechanisms and physiologic responses vary considerably across the developmental spectrum of childhood, bringing unique challenges to the management of pTBI. This is compounded further by complexity of neurodevelopmental changes influencing long-term outcomes. The foundation of current understanding of pTBI is laid on the innovative work done over the turn of the century. Incremental progress in the last few years has furthered our understanding of mechanisms, disease pathophysiology, recovery pathways and consequences from pTBI. There are developments in identification of biomarkers that can help diagnosis as well as predict outcomes more accurately to guide clinical decision making and track long-term outcomes. However, this progress has been slow, and more work is required to translate the large body of observational work into interventions to help improve outcomes from pTBI. This review aims to synthesise recent findings, evaluate existing evidence, and propose future research directions. Structured to first address key epidemiological and pathophysiological differences in the paediatric population with associated clinical challenges, followed by the potential role of physiological, blood and imaging biomarkers, this review seeks to provide a comprehensive update. Additionally, it addresses current evidence gaps in therapeutic strategies, rehabilitation needs and comprehensive systems of care, integrating insights from high and low resource settings. Finally, it reviews current research with a view to offer recommendations to reduce the evidence gaps in pTBI.
{"title":"Paediatric traumatic brain injury: unique population and unique challenges","authors":"Shruti Agrawal, Rebekah Mannix, Vicki Anderson, Miriam Beauchamp, Adam Ferguson, Lucia W Braga, Shu-Ling Chong, Anthony Figaji, Christopher Giza, David K Menon, Michael J Bell","doi":"10.1093/brain/awaf459","DOIUrl":"https://doi.org/10.1093/brain/awaf459","url":null,"abstract":"Paediatric traumatic brain injury (pTBI) remains a leading cause of death and disability in children around the world. The evidence to support pTBI management in children notably lags that in adult populations with a lack of data available to inform management. Injury mechanisms and physiologic responses vary considerably across the developmental spectrum of childhood, bringing unique challenges to the management of pTBI. This is compounded further by complexity of neurodevelopmental changes influencing long-term outcomes. The foundation of current understanding of pTBI is laid on the innovative work done over the turn of the century. Incremental progress in the last few years has furthered our understanding of mechanisms, disease pathophysiology, recovery pathways and consequences from pTBI. There are developments in identification of biomarkers that can help diagnosis as well as predict outcomes more accurately to guide clinical decision making and track long-term outcomes. However, this progress has been slow, and more work is required to translate the large body of observational work into interventions to help improve outcomes from pTBI. This review aims to synthesise recent findings, evaluate existing evidence, and propose future research directions. Structured to first address key epidemiological and pathophysiological differences in the paediatric population with associated clinical challenges, followed by the potential role of physiological, blood and imaging biomarkers, this review seeks to provide a comprehensive update. Additionally, it addresses current evidence gaps in therapeutic strategies, rehabilitation needs and comprehensive systems of care, integrating insights from high and low resource settings. Finally, it reviews current research with a view to offer recommendations to reduce the evidence gaps in pTBI.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"15 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145731091","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}
Óscar González-Velasco, Rosanna Parlato, Rüstem Yilmaz, Lorena Decker, Sonja Menge, Axel Freischmidt, Xiaoxu Yang, Nikshitha Tulasi, David Brenner, Peter M Andersen, Karin M E Forsberg, Johannes C M Schlachetzki, Benedikt Brors, Lena Voith von Voithenberg, Jochen H Weishaupt
Amyotrophic lateral sclerosis (ALS) is characterized by the progressive degeneration of cortical and spinal motor neurons. Mendelian germline mutations often cause familial ALS (fALS) but only approximately ten percent of sporadic ALS cases (sALS). We leveraged DNA and single cell RNA-sequencing data from autopsy tissue to explore the presence of somatic mosaic variants in sALS cases. Deep targeted panel sequencing of known ALS disease genes in motor cortex tissue revealed an enrichment of low allele frequency variants in sALS, but not in fALS with an identified monogenic cause. In silico analysis predicted increased pathogenicity of mosaic mutations in various known ALS mutational hot spots. In particular, we identified the somatic FUS variant p.E516X, located in an established hotspot for germline ALS mutations, which leads to nucleo-cytoplasmic mislocalization and aggregation typical for ALS FUS pathology. Additionally, we performed somatic variant calling on single cell RNA-sequencing data from sALS tissue and revealed a specific accumulation of somatic variants in excitatory neurons, reinforcing a neuron-autonomous disease initiation. Collectively, this study indicates that somatic mutations within the motor cortex, especially in excitatory neurons, may contribute to sALS development.
{"title":"Somatic gene mutations in the motor cortex of patients with sporadic amyotrophic lateral sclerosis","authors":"Óscar González-Velasco, Rosanna Parlato, Rüstem Yilmaz, Lorena Decker, Sonja Menge, Axel Freischmidt, Xiaoxu Yang, Nikshitha Tulasi, David Brenner, Peter M Andersen, Karin M E Forsberg, Johannes C M Schlachetzki, Benedikt Brors, Lena Voith von Voithenberg, Jochen H Weishaupt","doi":"10.1093/brain/awaf460","DOIUrl":"https://doi.org/10.1093/brain/awaf460","url":null,"abstract":"Amyotrophic lateral sclerosis (ALS) is characterized by the progressive degeneration of cortical and spinal motor neurons. Mendelian germline mutations often cause familial ALS (fALS) but only approximately ten percent of sporadic ALS cases (sALS). We leveraged DNA and single cell RNA-sequencing data from autopsy tissue to explore the presence of somatic mosaic variants in sALS cases. Deep targeted panel sequencing of known ALS disease genes in motor cortex tissue revealed an enrichment of low allele frequency variants in sALS, but not in fALS with an identified monogenic cause. In silico analysis predicted increased pathogenicity of mosaic mutations in various known ALS mutational hot spots. In particular, we identified the somatic FUS variant p.E516X, located in an established hotspot for germline ALS mutations, which leads to nucleo-cytoplasmic mislocalization and aggregation typical for ALS FUS pathology. Additionally, we performed somatic variant calling on single cell RNA-sequencing data from sALS tissue and revealed a specific accumulation of somatic variants in excitatory neurons, reinforcing a neuron-autonomous disease initiation. Collectively, this study indicates that somatic mutations within the motor cortex, especially in excitatory neurons, may contribute to sALS development.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"78 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145717320","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}
This scientific commentary refers to ‘White matter signals reflect information transmission between brain regions during seizures’ by Revell et al. (https://doi.org/10.1093/brain/awaf444).
{"title":"Beyond grey","authors":"Manuel Mercier","doi":"10.1093/brain/awaf461","DOIUrl":"https://doi.org/10.1093/brain/awaf461","url":null,"abstract":"This scientific commentary refers to ‘White matter signals reflect information transmission between brain regions during seizures’ by Revell et al. (https://doi.org/10.1093/brain/awaf444).","PeriodicalId":9063,"journal":{"name":"Brain","volume":"26 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145728738","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}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：