Growing evidence suggests that network hyperexcitability is a pivotal yet under-recognized pathology linking early Alzheimer's disease (AD) with mesial Temporal Lobe Epilepsy (mTLE). This narrative review synthesises pre-clinical and clinical data showing how disruption of excitation–inhibition balance, driven chiefly by the loss or dysfunction of parvalbumin- and somatostatin-positive GABAergic interneurons (INs), emerges early in AD and fosters subclinical epileptiform activity that hastens cognitive decline. We integrate findings that degeneration of Ventral Tegmental Area dopaminergic projections further destabilises hippocampal circuits by diminishing D2-mediated restraint of pyramidal firing and attenuating anti-inflammatory signalling. Convergent co-pathologies, soluble amyloid-β oligomers, tau mis-localisation, glutamate-dependent excitotoxicity and glia-mediated neuroinflammation amplify IN vulnerability and form a self-reinforcing loop of hyperexcitability, plasticity failure and neurodegeneration. Parallels with mTLE, where similar IN and dopaminergic deficits precipitate seizures, provide a mechanistic framework for interpreting EEG abnormalities and seizure susceptibility in prodromal AD. We critically appraise the therapeutic potential of interventions that restore excitation–inhibition balance or neuromodulatory tone, including interneuron-sparing agents, selective D2-like agonists, transcranial stimulation and anti-inflammatory or anti-excitotoxic strategies. By viewing early AD through a circuit-centric lens that bridges neurodegeneration and Epilepsy, we highlight testable biomarkers, propose stage-specific targets and argue that timely suppression of hyperexcitability could slow progression far upstream of irreversible neuronal loss. Such precision approaches may redefine disease modification by stabilizing vulnerable hippocampal networks before cognitive function is irrevocably compromised.
{"title":"Excitation–inhibition imbalance as a common thread linking early Alzheimer's disease with temporal lobe epilepsy","authors":"Nwife Getrude Okechukwu , Claudio Zaccone , Livia La Barbera , Annalisa Nobili , Marcello D'Amelio","doi":"10.1016/j.expneurol.2025.115581","DOIUrl":"10.1016/j.expneurol.2025.115581","url":null,"abstract":"<div><div>Growing evidence suggests that network hyperexcitability is a pivotal yet under-recognized pathology linking early Alzheimer's disease (AD) with mesial Temporal Lobe Epilepsy (mTLE). This narrative review synthesises pre-clinical and clinical data showing how disruption of excitation–inhibition balance, driven chiefly by the loss or dysfunction of parvalbumin- and somatostatin-positive GABAergic interneurons (INs), emerges early in AD and fosters subclinical epileptiform activity that hastens cognitive decline. We integrate findings that degeneration of Ventral Tegmental Area dopaminergic projections further destabilises hippocampal circuits by diminishing D2-mediated restraint of pyramidal firing and attenuating anti-inflammatory signalling. Convergent co-pathologies, soluble amyloid-β oligomers, tau mis-localisation, glutamate-dependent excitotoxicity and glia-mediated neuroinflammation amplify IN vulnerability and form a self-reinforcing loop of hyperexcitability, plasticity failure and neurodegeneration. Parallels with mTLE, where similar IN and dopaminergic deficits precipitate seizures, provide a mechanistic framework for interpreting EEG abnormalities and seizure susceptibility in prodromal AD. We critically appraise the therapeutic potential of interventions that restore excitation–inhibition balance or neuromodulatory tone, including interneuron-sparing agents, selective D2-like agonists, transcranial stimulation and anti-inflammatory or anti-excitotoxic strategies. By viewing early AD through a circuit-centric lens that bridges neurodegeneration and Epilepsy, we highlight testable biomarkers, propose stage-specific targets and argue that timely suppression of hyperexcitability could slow progression far upstream of irreversible neuronal loss. Such precision approaches may redefine disease modification by stabilizing vulnerable hippocampal networks before cognitive function is irrevocably compromised.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"397 ","pages":"Article 115581"},"PeriodicalIF":4.2,"publicationDate":"2025-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145654157","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 : 2025-11-25DOI: 10.1016/j.expneurol.2025.115568
Qingzhu Wang , Yanna Tong , Yuchuan Ding , Alexander Weiss , Aminah I. Fayyaz , Xiaokun Geng
Objectives
This study aims to identify the most optimal rehabilitation strategy for acute ischemic stroke recovery by examining the effects of different mobilization intensities and frequencies, and investigating the underlying mechanisms involving the HIF-1α/PLD2/mTOR signaling pathway.
Methods
A total of 152 adult male Sprague-Dawley rats were subjected to 2-h middle cerebral artery occlusion (MCAO) and divided into five groups to compare high-intensity exercise versus low-intensity exercise with interval (5 cycles of 5-min exercise and 5-min rest) versus continuous (30-min continuous exercise) sessions. The groups were as followed stroke-only, stroke with high-intensity-continuous (HC) exercise, stroke with high-intensity-interval (HI) exercise, stroke with low-intensity-continuous (LC) exercise, and stroke with low-intensity-interval (LI) exercise. Brain damage was assessed by measuring infarct volume, neurological deficits, and neuronal death. The long-term functional outcomes were evaluated using the adhesive tape touch, grid walk, Rota-rod, beam balance, and forelimb placing at days 7, 14, and 28. Neuroplasticity was measured by synaptogenesis [synaptophysin (SYN), post-synaptic density protein-95 (PSD-95)], and myelination [myelin-associated glycoprotein (MAG), myelin basic protein (MBP)]. The key role of regulatory molecules- hypoxia inducible factor 1α (HIF-1α), phospholipase D2 (PLD2), and the mechanistic target of rapamycin (mTOR) pathway- was also assessed.
Results
All exercise modalities significantly reduced infarct volumes, improved neurological deficits, and enhanced functional recovery (P< 0.05). In the low-intensity exercise groups, the LC rats showed a greater reduction in infarct volume and increased functional outcomes compared to the LI group (P< 0.05). Among the high-intensity exercise groups, long-term functional outcomes were significantly improved in the HI group compared to HC (P< 0.05). Both HI and LC significantly outperformed their counterparts in protecting hippocampal CA1 neurons, promoting synaptogenesis and myelination, and enhancing neuroplasticity signaling (P< 0.05). However, no major differences were observed between HI and LC in these outcomes. Activation of the HIF-1α/PLD2/mTOR pathway was identified as a key mechanism underlying the neuroplastic effects of rehabilitation, with HIF-1α inhibition further confirming its critical role.
Conclusion
Exercise rehabilitation, particularly the LC and HI protocols, significantly improves motor function post-stroke, likely through the HIF-1α/PLD2/mTOR pathway. These findings suggest that LC and HI exercise are promising clinical rehabilitation strategies for optimizing stroke recovery, warranting further clinical investigation.
{"title":"Optimizing functional recovery after acute ischemic stroke through intensity and frequency of rehabilitation: The critical role of HIF-1α/PLD2/mTOR signaling mechanisms","authors":"Qingzhu Wang , Yanna Tong , Yuchuan Ding , Alexander Weiss , Aminah I. Fayyaz , Xiaokun Geng","doi":"10.1016/j.expneurol.2025.115568","DOIUrl":"10.1016/j.expneurol.2025.115568","url":null,"abstract":"<div><h3>Objectives</h3><div>This study aims to identify the most optimal rehabilitation strategy for acute ischemic stroke recovery by examining the effects of different mobilization intensities and frequencies, and investigating the underlying mechanisms involving the HIF-1α/PLD2/mTOR signaling pathway.</div></div><div><h3>Methods</h3><div>A total of 152 adult male Sprague-Dawley rats were subjected to 2-h middle cerebral artery occlusion (MCAO) and divided into five groups to compare high-intensity exercise versus low-intensity exercise with interval (5 cycles of 5-min exercise and 5-min rest) versus continuous (30-min continuous exercise) sessions. The groups were as followed stroke-only, stroke with high-intensity-continuous (HC) exercise, stroke with high-intensity-interval (HI) exercise, stroke with low-intensity-continuous (LC) exercise, and stroke with low-intensity-interval (LI) exercise. Brain damage was assessed by measuring infarct volume, neurological deficits, and neuronal death. The long-term functional outcomes were evaluated using the adhesive tape touch, grid walk, Rota-rod, beam balance, and forelimb placing at days 7, 14, and 28. Neuroplasticity was measured by synaptogenesis [synaptophysin (SYN), post-synaptic density protein-95 (PSD-95)], and myelination [myelin-associated glycoprotein (MAG), myelin basic protein (MBP)]. The key role of regulatory molecules- hypoxia inducible factor 1α (HIF-1α), phospholipase D2 (PLD2), and the mechanistic target of rapamycin (mTOR) pathway- was also assessed.</div></div><div><h3>Results</h3><div>All exercise modalities significantly reduced infarct volumes, improved neurological deficits, and enhanced functional recovery (<em>P</em> <em><</em> 0.05). In the low-intensity exercise groups, the LC rats showed a greater reduction in infarct volume and increased functional outcomes compared to the LI group (<em>P</em> <em><</em> 0.05). Among the high-intensity exercise groups, long-term functional outcomes were significantly improved in the HI group compared to HC (<em>P</em> <em><</em> 0.05). Both HI and LC significantly outperformed their counterparts in protecting hippocampal CA1 neurons, promoting synaptogenesis and myelination, and enhancing neuroplasticity signaling (<em>P</em> <em><</em> 0.05). However, no major differences were observed between HI and LC in these outcomes. Activation of the HIF-1α/PLD2/mTOR pathway was identified as a key mechanism underlying the neuroplastic effects of rehabilitation, with HIF-1α inhibition further confirming its critical role.</div></div><div><h3>Conclusion</h3><div>Exercise rehabilitation, particularly the LC and HI protocols, significantly improves motor function post-stroke, likely through the HIF-1α/PLD2/mTOR pathway. These findings suggest that LC and HI exercise are promising clinical rehabilitation strategies for optimizing stroke recovery, warranting further clinical investigation.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"397 ","pages":"Article 115568"},"PeriodicalIF":4.2,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145622759","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 : 2025-11-25DOI: 10.1016/j.expneurol.2025.115569
Juquan Song , Balaji Krishnan , Nisha J. Garg
Burn injuries pose a substantial global health concern, impacting patients both acutely and profoundly in the long term. We elucidate key factors driving burn pathophysiology, moving beyond the initial wound to emphasize the resulting systemic cascade, highlighting the significant, often chronic, impact on multiple organ systems, and focusing on the Central Nervous System (CNS) as a critical mediator and target of pathology. Following the burn, the CNS develops persistent neuroinflammation and engages in detrimental, reciprocal interactions with cardiovascular, immune, endocrine, coagulation, skeletomuscular, and digestive systems, creating vicious cycles that can worsen the outcomes. We conclude with proposed future research directions, and stress the urgent need for integrated, interdisciplinary approaches bridging somatic and cerebral fields to fully comprehend the molecular mechanisms of this multi-organ crosstalk and develop effective therapies targeting the devastating long-term neurological and systemic consequences of burn injury.
{"title":"The impact of peripheral burn insult on the central nervous system","authors":"Juquan Song , Balaji Krishnan , Nisha J. Garg","doi":"10.1016/j.expneurol.2025.115569","DOIUrl":"10.1016/j.expneurol.2025.115569","url":null,"abstract":"<div><div>Burn injuries pose a substantial global health concern, impacting patients both acutely and profoundly in the long term. We elucidate key factors driving burn pathophysiology, moving beyond the initial wound to emphasize the resulting systemic cascade, highlighting the significant, often chronic, impact on multiple organ systems, and focusing on the Central Nervous System (CNS) as a critical mediator and target of pathology. Following the burn, the CNS develops persistent neuroinflammation and engages in detrimental, reciprocal interactions with cardiovascular, immune, endocrine, coagulation, skeletomuscular, and digestive systems, creating vicious cycles that can worsen the outcomes. We conclude with proposed future research directions, and stress the urgent need for integrated, interdisciplinary approaches bridging somatic and cerebral fields to fully comprehend the molecular mechanisms of this multi-organ crosstalk and develop effective therapies targeting the devastating long-term neurological and systemic consequences of burn injury.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"397 ","pages":"Article 115569"},"PeriodicalIF":4.2,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145622758","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 : 2025-11-24DOI: 10.1016/j.expneurol.2025.115566
Ye Pang , Hui Huang , Guangsheng Wang , Guangci Xu , Shiyuan Gu , Danyang Liu , Shuming Huang , Wenqi Mao , Yuning Liu , Fengqi Zhang , Yushan Hu , Guiyun Cui , Xingzhi Wang
Ischemic stroke causes significant neuronal DNA damage, but the mechanisms regulating DNA repair remain unclear. This study investigates the role of Ten-eleven translocase 3 (TET3) in DNA damage repair and its potential neuroprotective effects in ischemic stroke. Here we show that the TET3 protein level was significantly increased in the peri-infarct cortex of mice with transient middle cerebral artery occlusion (tMCAO). Knockdown of the TET3 gene significantly worsened neurological deficits and increased infarct volume in tMCAO mice, while TET3 overexpression exhibited the opposite effects and significantly enhanced neuronal DNA damage repair. Mechanistically, SUMO2-specific conjugation of TET3 at lysine residues K1188 and K1397 enhanced its nuclear localization, protein stability, and neuronal 5hmC levels. Furthermore, SUMOylated TET3 effectively reduced DNA damage and improved neurological outcomes following ischemic stroke, whereas a SUMO site-deficient mutant failed to confer these protective effects. Our study reveals a novel mechanism by which SUMOylated TET3 regulates neuronal DNA damage repair in ischemic stroke, strongly suggesting that upregulating TET3 SUMOylation in neurons may provide a promising therapeutic strategy to facilitate stroke recovery.
{"title":"TET3 SUMOylation enhances neuronal DNA damage repair and neuroprotection after ischemic stroke","authors":"Ye Pang , Hui Huang , Guangsheng Wang , Guangci Xu , Shiyuan Gu , Danyang Liu , Shuming Huang , Wenqi Mao , Yuning Liu , Fengqi Zhang , Yushan Hu , Guiyun Cui , Xingzhi Wang","doi":"10.1016/j.expneurol.2025.115566","DOIUrl":"10.1016/j.expneurol.2025.115566","url":null,"abstract":"<div><div>Ischemic stroke causes significant neuronal DNA damage, but the mechanisms regulating DNA repair remain unclear. This study investigates the role of Ten-eleven translocase 3 (TET3) in DNA damage repair and its potential neuroprotective effects in ischemic stroke. Here we show that the TET3 protein level was significantly increased in the peri-infarct cortex of mice with transient middle cerebral artery occlusion (tMCAO). Knockdown of the TET3 gene significantly worsened neurological deficits and increased infarct volume in tMCAO mice, while TET3 overexpression exhibited the opposite effects and significantly enhanced neuronal DNA damage repair. Mechanistically, SUMO2-specific conjugation of TET3 at lysine residues K1188 and K1397 enhanced its nuclear localization, protein stability, and neuronal 5hmC levels. Furthermore, SUMOylated TET3 effectively reduced DNA damage and improved neurological outcomes following ischemic stroke, whereas a SUMO site-deficient mutant failed to confer these protective effects. Our study reveals a novel mechanism by which SUMOylated TET3 regulates neuronal DNA damage repair in ischemic stroke, strongly suggesting that upregulating TET3 SUMOylation in neurons may provide a promising therapeutic strategy to facilitate stroke recovery.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"397 ","pages":"Article 115566"},"PeriodicalIF":4.2,"publicationDate":"2025-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145622714","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 : 2025-11-22DOI: 10.1016/j.expneurol.2025.115567
Miguel Cesar Merino-Ruiz , Jair Trapé Goulart , Gabriely dos Santos Penha , Ingrid Araújo de Santana , Márcia Renata Mortari
Deep brain stimulation (DBS) is an effective symptomatic therapy for Parkinson's disease (PD). Although unproven in humans, animal studies suggest that DBS, when applied beyond the acute phase of parkinsonism induction, may be neuroprotective. This study investigated motor responses and neuroprotection resulting from DBS initiated 24 h after induction of dopaminergic terminal loss via intrastriatal injection of 6-hydroxydopamine (6-OHDA) in mice. For that, three groups were analyzed: 6-OHDA/DBS-ON (n = 6) and 6-OHDA/DBS-OFF (n = 8), which received ipsilateral-to-lesion subthalamic nucleus (STN) DBS, implanted immediately after neurotoxin infusion, and Naive (n = 5), without interventions. 6-OHDA/DBS-ON received DBS for 4 days, 3 hours per day. The protocol began on day zero (D0). From D1 to D3, the Cylinder test was conducted. On D4, the Rotarod test was performed immediately before stimulation. Body mass was recorded daily until D4 and again on D7, before euthanasia. Tyrosine Hydroxylase (TH) immunohistochemistry was used to assess nigral neuronal loss and dopaminergic axon density in the striatum. The 6-OHDA/DBS-ON group showed less pronounced body mass loss from D0 to D4: −5.92 % (p = 0.22) vs. −18.04 % in 6-OHDA/DBS-OFF (p = 0.03). Additionally, during the 4 days of the protocol, the 6-OHDA/DBS-ON group exhibited a 3.88-fold superior impaired-limb use (p = 0.006) and a 17.14-fold improvement in Rotarod performance (p = 0.02). At the time of euthanasia (D7), the 6-OHDA/DBS-ON group had 82 % more nigral neurons (p = 0.03) and an 18.8 % higher lesioned/healthy striatal TH+ optical density ratio (p = 0.02). Altogether, the results indicate that early DBS attenuates disease progression and may contribute to neuroprotection in potential future premotor PD diagnosis scenarios.
{"title":"Early deep brain stimulation attenuates parkinsonism progression in a neurotoxin-induced Parkinson's disease mouse model","authors":"Miguel Cesar Merino-Ruiz , Jair Trapé Goulart , Gabriely dos Santos Penha , Ingrid Araújo de Santana , Márcia Renata Mortari","doi":"10.1016/j.expneurol.2025.115567","DOIUrl":"10.1016/j.expneurol.2025.115567","url":null,"abstract":"<div><div>Deep brain stimulation (DBS) is an effective symptomatic therapy for Parkinson's disease (PD). Although unproven in humans, animal studies suggest that DBS, when applied beyond the acute phase of parkinsonism induction, may be neuroprotective. This study investigated motor responses and neuroprotection resulting from DBS initiated 24 h after induction of dopaminergic terminal loss via intrastriatal injection of 6-hydroxydopamine (6-OHDA) in mice. For that, three groups were analyzed: 6-OHDA/DBS-ON (<em>n</em> = 6) and 6-OHDA/DBS-OFF (<em>n</em> = 8), which received ipsilateral-to-lesion subthalamic nucleus (STN) DBS, implanted immediately after neurotoxin infusion, and Naive (<em>n</em> = 5), without interventions. 6-OHDA/DBS-ON received DBS for 4 days, 3 hours per day. The protocol began on day zero (D0). From D1 to D3, the Cylinder test was conducted. On D4, the Rotarod test was performed immediately before stimulation. Body mass was recorded daily until D4 and again on D7, before euthanasia. Tyrosine Hydroxylase (TH) immunohistochemistry was used to assess nigral neuronal loss and dopaminergic axon density in the striatum. The 6-OHDA/DBS-ON group showed less pronounced body mass loss from D0 to D4: −5.92 % (<em>p</em> = 0.22) vs. −18.04 % in 6-OHDA/DBS-OFF (<em>p</em> = 0.03). Additionally, during the 4 days of the protocol, the 6-OHDA/DBS-ON group exhibited a 3.88-fold superior impaired-limb use (<em>p</em> = 0.006) and a 17.14-fold improvement in Rotarod performance (<em>p</em> = 0.02). At the time of euthanasia (D7), the 6-OHDA/DBS-ON group had 82 % more nigral neurons (<em>p</em> = 0.03) and an 18.8 % higher lesioned/healthy striatal TH+ optical density ratio (<em>p</em> = 0.02). Altogether, the results indicate that early DBS attenuates disease progression and may contribute to neuroprotection in potential future premotor PD diagnosis scenarios.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"397 ","pages":"Article 115567"},"PeriodicalIF":4.2,"publicationDate":"2025-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145596344","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}
Visual evoked potentials (VEPs) represent an accurate, fast, and cost-effective diagnostic tool to evaluate visual function in multiple sclerosis (MS), and its use in preclinical research can support longitudinal monitoring of treatments effects with implications for translational purposes. Anodal transcranial direct current stimulation (tDCS) and physical exercise (PE) are known to exert neuromodulatory effects on the central nervous system, increasing brain activity, promoting plasticity and remyelination. To improve our understanding of the effects of tDCS and PE on demyelination/remyelination processes and refine its therapeutic use in MS, VEPs were employed to monitor the mouse visual pathway during cuprizone (CPZ) demyelination including before and after therapeutic interventions. In CPZ-fed mice, VEP latency delays were associated with MBP loss in the dorsolateral geniculate nucleus (dLGN) confirming VEP as a biomarker of demyelination in the subcortical visual pathway. Combination of anodal tDCS and PE showed a strong beneficial effect on VEP latency during CPZ demyelination. Both VEP latency and behavioural motor function improvements were stronger after combined protocols, highlighting the potential of this multimodal approach in demyelinating conditions. Differential and synergistic contribution by anodal tDCS and PE was associated with reduced microglia/macrophage levels whilst effects on myelin by the first, and reduced cell death and BDNF protein were driven by the second. VEPs efficiency to detect modulation of visual function by brain stimulation and physical activity, strongly correlated with myelin changes in the visual pathway, providing a potent platform for the translatability of preclinical findings to the clinic.
{"title":"Tracking remyelination in a model of multiple sclerosis: Visual evoked potentials reveal therapeutic effect from brain stimulation and exercise","authors":"Elena Rossi , Silvia Marenna , Valerio Castoldi , Elena Criscuolo , Benedetta Giuliani , Chiara Malacrida , Nicola Clementi , Giancarlo Comi , Letizia Leocani","doi":"10.1016/j.expneurol.2025.115565","DOIUrl":"10.1016/j.expneurol.2025.115565","url":null,"abstract":"<div><div>Visual evoked potentials (VEPs) represent an accurate, fast, and cost-effective diagnostic tool to evaluate visual function in multiple sclerosis (MS), and its use in preclinical research can support longitudinal monitoring of treatments effects with implications for translational purposes. Anodal transcranial direct current stimulation (tDCS) and physical exercise (PE) are known to exert neuromodulatory effects on the central nervous system, increasing brain activity, promoting plasticity and remyelination. To improve our understanding of the effects of tDCS and PE on demyelination/remyelination processes and refine its therapeutic use in MS, VEPs were employed to monitor the mouse visual pathway during cuprizone (CPZ) demyelination including before and after therapeutic interventions. In CPZ-fed mice, VEP latency delays were associated with MBP loss in the dorsolateral geniculate nucleus (dLGN) confirming VEP as a biomarker of demyelination in the subcortical visual pathway. Combination of anodal tDCS and PE showed a strong beneficial effect on VEP latency during CPZ demyelination. Both VEP latency and behavioural motor function improvements were stronger after combined protocols, highlighting the potential of this multimodal approach in demyelinating conditions. Differential and synergistic contribution by anodal tDCS and PE was associated with reduced microglia/macrophage levels whilst effects on myelin by the first, and reduced cell death and BDNF protein were driven by the second. VEPs efficiency to detect modulation of visual function by brain stimulation and physical activity, strongly correlated with myelin changes in the visual pathway, providing a potent platform for the translatability of preclinical findings to the clinic.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"397 ","pages":"Article 115565"},"PeriodicalIF":4.2,"publicationDate":"2025-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145586532","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 : 2025-11-20DOI: 10.1016/j.expneurol.2025.115564
Christoph Erbacher , Aneeta Andrews , Till Sauerwein , Maximilian Breyer , Panagiota Arampatzi , Maximilian Koch , Stephanie Lamer , Tom Gräfenhan , Andreas Schlosser , Nurcan Üçeyler
Fabry disease (FD) is a rare genetic galactosidase alpha (GLA) gene associated lysosomal disorder caused by alpha-galactosidase A (AGAL) deficiency, leading to sphingolipid (globotriaosylceramide, Gb3) accumulation in multiple tissues. Burning pain due to small fiber neuropathy is an early symptom with great impact on health-related quality of life. The pathophysiological role of Gb3 accumulations in sensory neurons of the dorsal root ganglia is incompletely understood. We have differentiated induced pluripotent stem cells of an isogenic GLA knockout line (p.S364del, hemizygous) and its healthy control into sensory-like neurons to model FD in vitro. We have compared both lines on transcriptional and proteomic level and investigated the effects of AGAL enzyme supplementation. FD sensory neurons showed dysregulation of disease-related pathways, including axon guidance at both RNA and protein level and microfluidic assays revealed shorter neurite length. While AGAL did not restore the transcriptomic state, it reduced Gb3 accumulation and lowered protein ephrin 5 A and glycoprotein M6A level. These findings highlight axon guidance alterations in an isogenic human FD sensory neuron model, with potential implications for early central and peripheral innervation in small fiber neuropathy.
{"title":"Axon guidance deficits in a human sensory-like neuron model of Fabry disease","authors":"Christoph Erbacher , Aneeta Andrews , Till Sauerwein , Maximilian Breyer , Panagiota Arampatzi , Maximilian Koch , Stephanie Lamer , Tom Gräfenhan , Andreas Schlosser , Nurcan Üçeyler","doi":"10.1016/j.expneurol.2025.115564","DOIUrl":"10.1016/j.expneurol.2025.115564","url":null,"abstract":"<div><div>Fabry disease (FD) is a rare genetic galactosidase alpha (<em>GLA</em>) gene associated lysosomal disorder caused by alpha-galactosidase A (AGAL) deficiency, leading to sphingolipid (globotriaosylceramide, Gb3) accumulation in multiple tissues. Burning pain due to small fiber neuropathy is an early symptom with great impact on health-related quality of life. The pathophysiological role of Gb3 accumulations in sensory neurons of the dorsal root ganglia is incompletely understood. We have differentiated induced pluripotent stem cells of an isogenic <em>GLA</em> knockout line (p.S364del, hemizygous) and its healthy control into sensory-like neurons to model FD in vitro. We have compared both lines on transcriptional and proteomic level and investigated the effects of AGAL enzyme supplementation. FD sensory neurons showed dysregulation of disease-related pathways, including axon guidance at both RNA and protein level and microfluidic assays revealed shorter neurite length. While AGAL did not restore the transcriptomic state, it reduced Gb3 accumulation and lowered protein ephrin 5 A and glycoprotein M6A level. These findings highlight axon guidance alterations in an isogenic human FD sensory neuron model, with potential implications for early central and peripheral innervation in small fiber neuropathy.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"397 ","pages":"Article 115564"},"PeriodicalIF":4.2,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145581900","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 : 2025-11-19DOI: 10.1016/j.expneurol.2025.115562
Dustin T. Nguyen , Kate Mendoza , Cassandra Hall, Chunfeng Tan, Anjali Chauhan
Stroke is associated with autonomic dysfunction and reduced acetylcholine (ACh), a neurotransmitter critical for cognition. ACh signals in part through the alpha-7 nicotinic acetylcholine receptor (α7nAChR), a ligand-gated ion channel involved in synaptic plasticity, learning, and memory. Impaired α7nAChR signaling has been linked to heightened neuroinflammation and poor acute stroke recovery. Here, we investigated whether α7nAChR contributes to post-stroke cognitive recovery in young male mice. Wild-type (WT) and α7nAChR knockout (α7n0KO) mice underwent 60-min middle cerebral artery occlusion (MCAO). In a pharmacology cohort, the α7nAChR agonist GTS-21 was administered immediately after reperfusion and then daily for 20 days. Cognitive performance was assessed by novel object recognition (day 10), object location (day 20), and Barnes maze and open field testing (day 28). Mass spectrometry at 24 h quantified brain ACh. Flow cytometry at 24 h, 7 days, and 30 days measured microglial and brain F4/80 macrophages. Immunohistochemistry at day 30 evaluated gliosis and neurogenesis. WT mice showed reduced ipsilateral ACh and α7nAChR+ microglia with increased TNF-α versus sham. Compared with WT, α7n0KO mice exhibited greater myeloid infiltration at 24 h, fewer IL-6+microglia and F4/80+macrophages with impaired STAT3/SOCS3 signaling at day 7, and by day 30, reduced reparative microglia, fewer F4/80+ macrophages, greater tissue loss, demyelination, gliosis, reduced SVZ neurogenesis, and impaired cognitive recovery. GTS-21 treatment improved cognition and reduced gliosis, supporting a protective role for α7nAChR activation. In conclusion, α7nAChR signaling supports reparative immune programs and promotes neurorepair after stroke, thereby enhancing long-term cognitive recovery.
{"title":"Alpha 7 nicotinic acetylcholine receptor contributes to long-term cognitive recovery following ischemic stroke","authors":"Dustin T. Nguyen , Kate Mendoza , Cassandra Hall, Chunfeng Tan, Anjali Chauhan","doi":"10.1016/j.expneurol.2025.115562","DOIUrl":"10.1016/j.expneurol.2025.115562","url":null,"abstract":"<div><div>Stroke is associated with autonomic dysfunction and reduced acetylcholine (ACh), a neurotransmitter critical for cognition. ACh signals in part through the alpha-7 nicotinic acetylcholine receptor (α7nAChR), a ligand-gated ion channel involved in synaptic plasticity, learning, and memory. Impaired α7nAChR signaling has been linked to heightened neuroinflammation and poor acute stroke recovery. Here, we investigated whether α7nAChR contributes to post-stroke cognitive recovery in young male mice. Wild-type (WT) and α7nAChR knockout (α7n<sup>0</sup>KO) mice underwent 60-min middle cerebral artery occlusion (MCAO). In a pharmacology cohort, the α7nAChR agonist GTS-21 was administered immediately after reperfusion and then daily for 20 days. Cognitive performance was assessed by novel object recognition (day 10), object location (day 20), and Barnes maze and open field testing (day 28). Mass spectrometry at 24 h quantified brain ACh. Flow cytometry at 24 h, 7 days, and 30 days measured microglial and brain F4/80 macrophages. Immunohistochemistry at day 30 evaluated gliosis and neurogenesis. WT mice showed reduced ipsilateral ACh and α7nAChR<sup>+</sup> microglia with increased TNF-α versus sham. Compared with WT, α7n<sup>0</sup>KO mice exhibited greater myeloid infiltration at 24 h, fewer IL-6<sup>+</sup>microglia and F4/80<sup>+</sup>macrophages with impaired STAT3/SOCS3 signaling at day 7, and by day 30, reduced reparative microglia, fewer F4/80<sup>+</sup> macrophages, greater tissue loss, demyelination, gliosis, reduced SVZ neurogenesis, and impaired cognitive recovery. GTS-21 treatment improved cognition and reduced gliosis, supporting a protective role for α7nAChR activation. In conclusion, α7nAChR signaling supports reparative immune programs and promotes neurorepair after stroke, thereby enhancing long-term cognitive recovery.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"397 ","pages":"Article 115562"},"PeriodicalIF":4.2,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145573036","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 : 2025-11-19DOI: 10.1016/j.expneurol.2025.115563
Yunsha Zhang , Xiaodan Bai , Penglin Yin , Yuying Guo , Liji Yang , Songlin Li , Xiaoxiao Zhao , Junjie Su , Aiqin Zhong , Linna Zhao , Shixin Xu
Cognitive impairment is a common sequela of ischemic stroke, primarily driven by disrupted synaptic structural plasticity in the hippocampus. Although bone marrow mesenchymal stem cell-derived extracellular vesicles (BMSC-EVs) are known to promote synaptic plasticity, their heterogeneous effects across hippocampal subregions and associated regulatory mechanisms remain unclear. In this study, BMSC-EVs were intravenously administered 24 h post-reperfusion in a rat model of transient middle cerebral artery occlusion (tMCAO), with additional injections on days 3, 5, and 7. Behavioral assessments (mNSS, Morris Water Maze, Y-maze) showed significant improvements in neurological and cognitive functions (P < 0.05). Histological observation and analyses revealed differential synaptic remodeling. The dentate gyrus (DG) exhibited the most pronounced response, including a significant increase in spine density beyond sham levels (P < 0.01), a shift towards mature spine morphologies, and enhanced axonal integrity as indicated by NF200 expression (P < 0.001). The CA3 region showed improved neuronal survival (P < 0.05), dendritic complexity, and elevated expression of Syn and PSD-95 (P < 0.01 and P < 0.001, respectively). In contrast, the CA1 region displayed limited structural recovery, despite moderate yet significant increases in Syn and PSD-95 expression (P < 0.001). Mechanistically, BMSC-EVs restored ischemia-induced downregulation of Semaphorin 3G (Sema3G), Neuropilin-2 (Nrp2), and PlexinA4 (P < 0.05 to P < 0.001), suggesting a correlation between BMSC-EVs treatment and activation of the Sema3G-Nrp2/PlexinA4 signaling pathway, which may facilitate neurovascular interactions crucial for synaptic remodeling. In conclusion, this study demonstrates that BMSC-EVs enhance hippocampal synaptic plasticity in a region-distinct manner, with the DG and CA3 regions showing the most robust response. These effects are associated with synaptic protein regulation and the Sema3G-Nrp2/PlexinA4 axis.
{"title":"BMSC-EVs improve post-stroke cognition by promoting regionally distinct synaptic repair via Sema3G-Nrp2/PlexinA4 Signaling","authors":"Yunsha Zhang , Xiaodan Bai , Penglin Yin , Yuying Guo , Liji Yang , Songlin Li , Xiaoxiao Zhao , Junjie Su , Aiqin Zhong , Linna Zhao , Shixin Xu","doi":"10.1016/j.expneurol.2025.115563","DOIUrl":"10.1016/j.expneurol.2025.115563","url":null,"abstract":"<div><div>Cognitive impairment is a common sequela of ischemic stroke, primarily driven by disrupted synaptic structural plasticity in the hippocampus. Although bone marrow mesenchymal stem cell-derived extracellular vesicles (BMSC-EVs) are known to promote synaptic plasticity, their heterogeneous effects across hippocampal subregions and associated regulatory mechanisms remain unclear. In this study, BMSC-EVs were intravenously administered 24 h post-reperfusion in a rat model of transient middle cerebral artery occlusion (tMCAO), with additional injections on days 3, 5, and 7. Behavioral assessments (mNSS, Morris Water Maze, Y-maze) showed significant improvements in neurological and cognitive functions (<em>P</em> < 0.05). Histological observation and analyses revealed differential synaptic remodeling. The dentate gyrus (DG) exhibited the most pronounced response, including a significant increase in spine density beyond sham levels (<em>P</em> < 0.01), a shift towards mature spine morphologies, and enhanced axonal integrity as indicated by NF200 expression (<em>P</em> < 0.001). The CA3 region showed improved neuronal survival (<em>P</em> < 0.05), dendritic complexity, and elevated expression of Syn and PSD-95 (<em>P</em> < 0.01 and <em>P</em> < 0.001, respectively). In contrast, the CA1 region displayed limited structural recovery, despite moderate yet significant increases in Syn and PSD-95 expression (<em>P</em> < 0.001). Mechanistically, BMSC-EVs restored ischemia-induced downregulation of Semaphorin 3G (Sema3G), Neuropilin-2 (Nrp2), and PlexinA4 (<em>P</em> < 0.05 to <em>P</em> < 0.001), suggesting a correlation between BMSC-EVs treatment and activation of the Sema3G-Nrp2/PlexinA4 signaling pathway, which may facilitate neurovascular interactions crucial for synaptic remodeling. In conclusion, this study demonstrates that BMSC-EVs enhance hippocampal synaptic plasticity in a region-distinct manner, with the DG and CA3 regions showing the most robust response. These effects are associated with synaptic protein regulation and the Sema3G-Nrp2/PlexinA4 axis.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"397 ","pages":"Article 115563"},"PeriodicalIF":4.2,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145573037","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}
Alzheimer's disease (AD) is a disorder characterized by progressive cognitive impairment. Syringic acid (SA) is a phenolic compound with many beneficial effects, such as antioxidant, anti-inflammatory, anti-diabetic, anti-carcinogenic, and neuroprotective. Our study aimed to investigate the effects of SA (50 mg/kg/day) on scopolamine (SCO)-induced AD-like condition in rats. Immunohistochemical evaluation was performed using antibodies to postsynaptic density protein 95 (PSD-95), Glycogen synthase kinase-3β (GSK-3β), TNF-α, and caspase-3. The hippocampus was stained with Hematoxylin-Eosin, and the total number of hippocampal neurons and hippocampal volume were calculated using the stereological method. The Y-maze task behavioral test was performed. SCO decreased PSD-95 expression while increasing GSK-3β, TNF-α, and caspase-3 expression. SA treatment increased PSD-95 expression while decreasing GSK-3β, TNF-α, and caspase-3 expression. Compared to the control group, the number of hippocampal neurons was significantly decreased in the Alzheimer's group, but the number of neurons in the SA group was significantly higher than in the Alzheimer's group. Hippocampal volume was lower in the Alzheimer's group, although there was no statistical difference between the groups. SA also improved SCO-induced cognitive impairment. Our study findings suggest that SA may mitigate SCO-induced cognitive impairment in the AD rat model, modulating PSD-95 and GSK-3β and decreasing neuroinflammation and apoptosis.
{"title":"Syringic acid mitigates scopolamine-induced cognitive impairment by regulating PSD-95 and GSK-3β and by preventing neurodegeneration in an Alzheimer-like rat model","authors":"Fikret Altındağ , Mehmet Hafit Bayır , Jamal Khalid Ismael Alhalboosi , Kenan Yıldızhan","doi":"10.1016/j.expneurol.2025.115556","DOIUrl":"10.1016/j.expneurol.2025.115556","url":null,"abstract":"<div><div>Alzheimer's disease (AD) is a disorder characterized by progressive cognitive impairment. Syringic acid (SA) is a phenolic compound with many beneficial effects, such as antioxidant, anti-inflammatory, anti-diabetic, anti-carcinogenic, and neuroprotective. Our study aimed to investigate the effects of SA (50 mg/kg/day) on scopolamine (SCO)-induced AD-like condition in rats. Immunohistochemical evaluation was performed using antibodies to postsynaptic density protein 95 (PSD-95), Glycogen synthase kinase-3β (GSK-3β), TNF-α, and caspase-3. The hippocampus was stained with Hematoxylin-Eosin, and the total number of hippocampal neurons and hippocampal volume were calculated using the stereological method. The Y-maze task behavioral test was performed. SCO decreased PSD-95 expression while increasing GSK-3β, TNF-α, and caspase-3 expression. SA treatment increased PSD-95 expression while decreasing GSK-3β, TNF-α, and caspase-3 expression. Compared to the control group, the number of hippocampal neurons was significantly decreased in the Alzheimer's group, but the number of neurons in the SA group was significantly higher than in the Alzheimer's group. Hippocampal volume was lower in the Alzheimer's group, although there was no statistical difference between the groups. SA also improved SCO-induced cognitive impairment. Our study findings suggest that SA may mitigate SCO-induced cognitive impairment in the AD rat model, modulating PSD-95 and GSK-3β and decreasing neuroinflammation and apoptosis.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"396 ","pages":"Article 115556"},"PeriodicalIF":4.2,"publicationDate":"2025-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145556267","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}
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号