Neurotherapeutics最新文献

{"title":"Antibody targeting TDP-43 mitigates pathogenic pathways induced by the cerebrospinal fluid of ALS.","authors":"Amélie Poulin-Brière, Silvia Pozzi, Jean-Pierre Julien","doi":"10.1016/j.neurot.2025.e00737","DOIUrl":"https://doi.org/10.1016/j.neurot.2025.e00737","url":null,"abstract":"<p><p>Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease characterized by the cytoplasmic mislocalization and accumulation of TAR DNA binding protein 43 (TDP-43). We reported previously the protective effects in a transgenic mouse model expressing ALS-linked mutant TDP-43^A315T of a monoclonal antibody, called E6, binding specifically to the RNA Recognition Motif 1 (RRM1) domain of TDP-43. Here, we tested the effects of E6 antibody in an animal model of sporadic ALS based on the intracerebroventricular (i.c.v.) infusion during 14 days of cerebrospinal fluid (CSF) from sporadic ALS patients into transgenic mice expressing human TDP-43^WT. Either intrathecal (i.t.) or i.c.v. injection of E6 antibody conferred protective effects in this model of disease. Thus, the CSF-inoculated E6 antibody reduced motor and cognitive impairments, mitigated TDP-43 proteinopathy and prevented neurofilament (Nf) disorganization in cortical and spinal neurons. Administration of E6 antibody reduced the loss of motor neurons in the spinal cord and the denervation of neuromuscular junctions. Moreover, E6 antibody promoted a switch toward features associated with a protective phenotype of microglial activation characterized by enhanced phagocytic function and reduced secretion of pro-inflammatory cytokines. The results suggest that an immunotherapy targeting the RRM1 domain of TDP-43 may confer protection against pathogenic pathways triggered by the CSF of ALS patients.</p>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":" ","pages":"e00737"},"PeriodicalIF":6.9,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145054858","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":"Targeted ErbB4 receptor activation ameliorates neuronal deficits via DOCK3 signaling in a transgenic mouse AD model.","authors":"Chong Liu, Yan Zhao, Ji-Ji Dao, Wei Zhang, Jie Liu, Yu-Ke Ma, Chen-Meng Qiao, Chun Cui, Shuang-Xi Chen, Yan-Qin Shen, Wei-Jiang Zhao","doi":"10.1016/j.neurot.2025.e00739","DOIUrl":"https://doi.org/10.1016/j.neurot.2025.e00739","url":null,"abstract":"<p><p>Accumulating evidence has highlighted the critical involvement of ErbB4 receptor in the onset and progression of Alzheimer's disease (AD). Utilizing a small molecule ErbB4 receptor agonist (E4A) identified through virtual screening, it was observed that activation of ErbB4 receptor significantly ameliorated the cognitive behavioral deficits in APP/PS1 mice. Additionally, E4A treatment enhanced the expression of DOCK3 and SIRT3, leading to improvements in synaptic and mitochondrial dysfunction within the hippocampus of these mice. E4A also attenuated the activation of the TLR4-NF-κB-NLRP3 pathway, thereby reducing neuroinflammation and the formation of β-amyloid (Aβ) plaques. In vitro studies revealed that E4A partially mitigated the impact of hippocampal neuronal damage on microglial inflammation, which was partly compromised by the silencing of DOCK3. Collectively, our data suggest that targeted activation of ErbB4 receptor may treat AD via DOCK3 signaling by inhibiting neuronal damage and subsequent neuroinflammation, thereby offering a viable strategy for this neurodegenerative disease.</p>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":" ","pages":"e00739"},"PeriodicalIF":6.9,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145054836","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":"The polyunsaturated fatty acid and oxylipin plasma signature of aneurysmal subarachnoid haemorrhage, case-control study.","authors":"M A Franssen, M A Tjerkstra, M Heijink, S A Rotman, D Verbaan, E van Bavel, W P Vandertop, H E de Vries, J M Coutinho, M A Giera, I A Mulder, G Kooij","doi":"10.1016/j.neurot.2025.e00736","DOIUrl":"https://doi.org/10.1016/j.neurot.2025.e00736","url":null,"abstract":"<p><p>Delayed cerebral ischemia (DCI) following aneurysmal subarachnoid haemorrhage (aSAH) is a complex and acute condition with limited options for early detection and effective treatments. The plasma levels of individual polyunsaturated fatty acids (PUFA) and their bioactive metabolites (oxylipins) of aSAH patients both at admission and over time remain largely unexplored, particularly concerning the development of DCI. In this study, plasma samples of aSAH patients were collected at admission and on days 4, 10, and 21 post-admission. ASAH patients who did not develop DCI were age- and sex matched to aSAH patients who did develop DCI. Control groups included patients with an unruptured aneurysm (UA) and healthy controls (HC). PUFA and oxylipin levels in plasma were measured using liquid chromatography with tandem mass spectrometry and were analysed using non-parametric univariate tests. At admission, aSAH (n ​= ​47) patients showed elevated levels of several PUFAs, such as linoleic acid and arachidonic acid, as well as oxylipins, including 12-HETE, 20-HETE and 19,20-DiHDPA, compared to UA (n ​= ​24) and HC (n ​= ​13). 12-HETE was predominantly found in the S-configuration, indicating synthesis via 12(S)-lipoxygenase. PUFA and oxylipin levels dropped significantly by day four post-admission, except for 19,20-DiHDPA. No PUFAs or oxylipins differentiated patients who developed DCI. We characterized a distinct plasma PUFA- and oxylipin profile in aSAH patients at admission and identified a significant decline in PUFA and oxylipin levels by day 4 post-admission.</p>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":" ","pages":"e00736"},"PeriodicalIF":6.9,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145040856","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":"Talin 1 plays a significant role in the development of tolerogenic dendritic cells, which may contribute to the progression of multiple sclerosis.","authors":"Kouichi Ito","doi":"10.1016/j.neurot.2025.e00731","DOIUrl":"https://doi.org/10.1016/j.neurot.2025.e00731","url":null,"abstract":"","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":" ","pages":"e00731"},"PeriodicalIF":6.9,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145033694","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":"The GPR120 agonist TUG-891 mitigates ischemic brain injury by attenuating endoplasmic reticulum stress and apoptosis via the PI3K/AKT signaling pathway.","authors":"Panxi Sun, Lili Wei, Xue Qin, Jia Luo, Dongsheng Fan, Yong Chen","doi":"10.1016/j.neurot.2025.e00735","DOIUrl":"https://doi.org/10.1016/j.neurot.2025.e00735","url":null,"abstract":"<p><p>Extensive research has confirmed that omega-3 fatty acids provide cardiovascular protection primarily by activating the G protein-coupled receptor 120 (GPR120) signaling pathway. However, natural activators of this receptor often lack sufficient strength and precision. TUG-891, a recently synthesized selective GPR120 activator, has displayed significant therapeutic potential in multiple disease. This investigation seeks to evaluate the neuroprotective effects of TUG-891 against ischemic cerebral injury. To this end, an in vivo murine model of distal middle cerebral artery occlusion (dMCAO) was employed, alongside an in vitro model utilizing oxygen-glucose deprivation/reperfusion in HT22 ​cells. The results indicated that TUG-891 significantly enhanced neurological function, reduced the volume of cerebral infarction, and alleviated pathological damage following dMCAO. Moreover, TUG-891 demonstrated a significant reduction in oxidative stress levels, a decrease of markers related to endoplasmic reticulum (ER) stress, and the modulation of critical apoptotic regulators, thereby inhibiting apoptosis in both in vivo and in vitro settings. Additionally, TUG-891 was found to affect the PI3K/Akt signaling pathway, with the application of the inhibitor LY294002 negating the protective effects of TUG-891 in vitro. This comprehensive study reveals TUG-891's therapeutic potential for ischemic stroke through multi-target mechanisms involving oxidative stress mitigation, ER stress regulation, and survival pathway activation. The consistent neuroprotection observed across biological models underscores its translational value for further clinical development.</p>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":" ","pages":"e00735"},"PeriodicalIF":6.9,"publicationDate":"2025-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145015859","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":"Two roads diverged in multiple sclerosis: When is switching therapy effective?","authors":"Anthony T Reder","doi":"10.1016/j.neurot.2025.e00734","DOIUrl":"https://doi.org/10.1016/j.neurot.2025.e00734","url":null,"abstract":"","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":" ","pages":"e00734"},"PeriodicalIF":6.9,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145008405","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":"Efficacy and safety of efgartigimod versus intravenous immunoglobulin in early intervention of acetylcholine receptor antibody-positive impending myasthenic crisis: A retrospective cohort study.","authors":"Rongjing Guo, Chao Sun, Xiaoxi Huang, Sijia Hao, Qingqing Wang, Zhe Ruan, Ting Gao, Yonglan Tang, Xiangqi Cao, Yu Liu, Zhuyi Li, Ting Chang","doi":"10.1016/j.neurot.2025.e00730","DOIUrl":"https://doi.org/10.1016/j.neurot.2025.e00730","url":null,"abstract":"<p><p>Early intervention in impending myasthenic crisis (IMC) is critical to avert life-threatening progression. This study compared the clinical effectiveness and safety of the novel FcRn antagonist efgartigimod versus intravenous immunoglobulin (IVIg) in IMC management. In this retrospective cohort study, we analyzed 51 acetylcholine receptor antibody-positive (AChR-Ab+) IMC patients who received either efgartigimod (n ​= ​30) or IVIg (n ​= ​21) from June 2023 to November 2024. Efficacy was assessed based on changes in Myasthenia Gravis Activities of Daily Living (MG-ADL) and Quantitative Myasthenia Gravis (QMG) scores over four weeks. From weeks 2-4, the efgartigimod group showed significantly greater improvements in MG-ADL and QMG scores (both P ​< ​0.05), with a similar trend after baseline adjustment. By week 4, the results of the clinically meaningful improvement (CMI) analysis indicated that a higher proportion of patients in the efgartigimod group achieved MG-ADL improvement ≥7 points (90.0 ​% vs. 57.1 ​%) and greater QMG scores improvement. The proportion of patients reaching minimal symptom expression (MSE) was 80.0 ​% in the efgartigimod group compared to 14.3 ​% in the IVIg group, with mean improvement rates of 91.5 ​% vs. 60.7 ​%, respectively. One case of myasthenic crisis-related death occurred in the IVIg group, while no severe adverse events were reported in the remaining patients. Efgartigimod has been shown to effectively alleviate IMC symptoms, prevent progression to myasthenic crisis (MC), and significantly reduce in complications without substantially increasing the economic costs. These findings suggest its potential as a first-line therapeutic option for AChR-Ab-positive IMC patients.</p>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":" ","pages":"e00730"},"PeriodicalIF":6.9,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145008353","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":"PROTACs therapeutically target the polyglutamine androgen receptor in spinal and bulbar muscular atrophy models.","authors":"Agamjot Sangotra, Satya L Reddy, Curtis J Kuo, Weiguo Xiang, Diane E Merry, Christopher Grunseich, Shaomeng Wang, Andrew P Lieberman","doi":"10.1016/j.neurot.2025.e00732","DOIUrl":"https://doi.org/10.1016/j.neurot.2025.e00732","url":null,"abstract":"<p><p>Spinal and bulbar muscular atrophy (SBMA) is a CAG/polyglutamine (polyQ) repeat expansion disorder in which the mutant androgen receptor (AR) protein triggers progressive degeneration of the neuromuscular system in men. As the misfolded polyQ AR is the proximal mediator of toxicity, therapeutic efforts have focused on targeting the mutant protein, but these prior efforts have met with limited success in SBMA patients. Here, we examine the efficacy of small molecule AR proteolysis-targeting chimera (PROTAC) degraders that rapidly and potently promote AR ubiquitination and degradation by the proteasome. We show that the AR PROTAC degrader ARD-1676 clears polyQ AR in an over-expression system, in patient iPSC-derived induced motor neurons and skeletal muscle cells, and in a gene targeted mouse model of disease. Furthermore, we demonstrate that 24-h treatment with ARD-1676 rescues transcriptional dysregulation in SBMA induced skeletal muscle cells. These data provide evidence of therapeutic efficacy and in vivo target engagement, establishing AR PROTAC degraders as potential therapeutic agents for the treatment of SBMA.</p>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":" ","pages":"e00732"},"PeriodicalIF":6.9,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145006399","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":"Cellular fibronectin exacerbates α-synuclein aggregation via integrin alpha4beta1 mediated PARP1 and SCD elevation.","authors":"Zifeng Huang, Hui Zhong, Yingqiong Lu, Ruoyang Yu, Muwei Zhang, Jialing Zheng, Bin Xiao, Zhidong Zhou, Yinghua Yu, Chao Deng, Kunlin Jin, Shuzhen Zhu, Chong Li, Xiaoying Cui, Karolina Poplawska-Domaszewicz, K Ray Chaudhuri, Eng-King Tan, Qing Wang","doi":"10.1016/j.neurot.2025.e00729","DOIUrl":"https://doi.org/10.1016/j.neurot.2025.e00729","url":null,"abstract":"<p><p>Mitochondrial dysfunction and lipid metabolic disturbance may promote pathologic α-synuclein (α-syn) aggregation, accelerating the progression of Parkinson's disease (PD). Whether extracellular matrices are associated with those pathological mechanisms in PD remains elusive. Here, we aimed to identify if cellular fibronectin (cFn), a component of extracellular matrices, contributes to α-syn abnormality via inducing mitochondrial energy depletion or disrupting lipid homeostasis. In Our study, 1-methyl-4-phenyl-1, 2,3,6-tetrahydropyridine (MPTP)-treated PD mice and human neuronal SH-SY5Y cells were used. Astrocyte-derived cFn protein delivery and AAV-mediated cFn knockdown mouse models were established to validate the functional role of cFn. Mitochondrial dysfunction was detected by transmission electron microscopy (TEM), and the level of poly (ADP‒ribose) (PAR) polymerase-1(PARP1), pathologic α-syn and cFn-induced lipid dysmetabolism was determined. We demonstrated that excessive cFn accumulated in the SNpc of MPTP-treated mice, and cFn rather than plasma Fn (pFn) exacerbated neuronal mitochondrial dysfunction and α-syn accumulation. Mechanically, cFn induced PARP1 activation via integrin α4β1, which contributed to neuronal NAD ​+ ​depletion and pathologic α-syn aggregation. Furthermore, cFn induced an increase in free fatty acids (FAs) and triglycerides (TAG) in neurons by binding to integrin α4β1, which synergistically contributed to α-syn abnormality. We revealed that cFn induced stearoyl-CoA desaturase (SCD) activation via integrin α4β1, which was interacted with SCD. Genetically depleting cFn suppressed PARP1 activation and SCD elevation, which further rescued the mitochondrial disruption and α-syn abnormalities in MPTP-treated mice. Overall, our findings suggest that cFn exacerbates α-syn aggregation via integrin α4β1-mediated PARP1 and SCD elevation. cFn-targeting therapy may be a promising strategy for treating PD.</p>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":" ","pages":"e00729"},"PeriodicalIF":6.9,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145006370","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":"Safety and efficacy of Igk-TATk-CDKL5 gene therapy in mosaic CDKL5 deficiency.","authors":"Giorgio Medici, Marianna Tassinari, Manuela Loi, Angelica Marina Bove, Beatrice Casadei Garofani, Greta Volpedo, Nicola Mottolese, Gabriele Matteoli, Viviana Lo Martire, Chiara Berteotti, Giulia Candini, Federica Trebbi, Antonella Riva, Pasquale Striano, Giovanna Zoccoli, Giulia Curia, Stefania Trazzi, Elisabetta Ciani","doi":"10.1016/j.neurot.2025.e00727","DOIUrl":"10.1016/j.neurot.2025.e00727","url":null,"abstract":"<p><p>CDKL5 Deficiency Disorder (CDD) is a severe neurodevelopmental disorder caused by mutations in the X-linked CDKL5 gene, resulting in early-onset seizures, developmental delays, and cognitive and sensorimotor impairments. While emerging therapies show promise, substantial challenges remain in developing a cure for CDD. In our prior work, we developed an innovative gene therapy strategy based on an Igk-TATk-CDKL5 fusion protein, which enhances brain distribution of the therapeutic protein, significantly improving treatment efficacy in a Cdkl5 knockout male mouse model. However, CDKL5 dosage sensitivity may pose challenges in patients with mosaic loss of CDKL5 function, potentially limiting the treatment's effectiveness or even exacerbating clinical symptoms. In this study, we aimed to address this gap by evaluating the safety and efficacy of Igk-TATk-CDKL5 therapy in a heterozygous female mouse model (Cdkl5 +/-), which better represents the majority of human CDD patients. We found that introducing Igk-TATk-CDKL5 significantly improved behavioral phenotypes and corrected brain structural defects, such as dendritic morphology and connectivity. Importantly, no adverse effects were observed in the brain or peripheral organs (e.g., the heart), indicating that CDKL5 overexpression in the heterozygous condition was well tolerated. These findings support the therapeutic potential of Igk-TATk-CDKL5 and suggest that a possible cross-correction mechanism may contribute to its efficacy, even in the context of mosaic CDKL5 deficiency. This approach may therefore offer promising therapeutic outcomes for patients with CDD.</p>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":" ","pages":"e00727"},"PeriodicalIF":6.9,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144992984","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}