NeuroMolecular Medicine最新文献

{"title":"B4Galnt1 Deficiency Reverses Severe Neurological Symptoms in a Mouse Model of Tay-Sachs Disease.","authors":"Selman Yanbul, Tufan Utku Calıskan, Mustafa Can Turali, Volkan Seyrantepe","doi":"10.1007/s12017-026-08916-x","DOIUrl":"10.1007/s12017-026-08916-x","url":null,"abstract":"","PeriodicalId":19304,"journal":{"name":"NeuroMolecular Medicine","volume":"28 1","pages":""},"PeriodicalIF":3.9,"publicationDate":"2026-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12971821/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147390666","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Miro1 in Parkinson's Disease: A Key Regulator of Mitochondrial Homeostasis and Neurodegeneration.","authors":"Gaurav Singh, Simranpreet Kaur, Khadga Raj Aran","doi":"10.1007/s12017-026-08917-w","DOIUrl":"10.1007/s12017-026-08917-w","url":null,"abstract":"<p><p>Parkinson's disease (PD), is slowly advancing disease condition of the nervous system, which leads to interruption of normal motor function, resulting in symptoms such as tremor, muscle rigidity, bradykinesia, and postural instability. PD is commonly also accompanied by motor impairment, associated with broad non-motor symptoms, of which sensory prob 21qwlems are including behavioural and sleeping disorders and autonomic dysfunctions. The disease is characterised by slow degeneration of the dopaminergic neurons in the substantia nigra pars compacta (SNpc), and pathological misfolded α-synuclein (α-syn) deposition protein. Mitochondrial Rho GTPase (Miro1) is one of the major regulators of neuronal energy transport, mitochondrial motility, and communication in the central nervous system (CNS). It also regulates the quality of mitochondria in their interaction with regulatory proteins, PTEN-induced kinase 1 (PINK1), Parkin, and Leucine-rich repeat kinase2 (LRRK2). Studies stated that there are a few PD-related genes that are correlated with Miro1, which influences its activity. The dysregulation or genetic mutations of Miro1 disrupt the mitochondrial activities, including the transport, mitophagy, and calcium (Ca²⁺) homeostasis, particularly among dopaminergic neurons. These imbalances augment oxidative stress, mitochondrial dysfunction, and α-syn aggregation, which eventually regulate neuron exposure and are a risk factor in the development of PD. This review highlights the role of Miro1 in the development and pathophysiology of PD, with particular emphasis on recent experimental and clinical findings. It also focuses on the therapeutic prospect of Miro1-targeted approaches as new emerging interventions to reduce the development of the disease.</p>","PeriodicalId":19304,"journal":{"name":"NeuroMolecular Medicine","volume":"28 1","pages":""},"PeriodicalIF":3.9,"publicationDate":"2026-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147369856","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Early-Age Cuprizone Exposure Induces Region-Specific Demyelination and Neuroinflammation in Mice.","authors":"May Rokach, Gilad Levy, Galit Elad-Sfadia, Boaz Barak","doi":"10.1007/s12017-026-08911-2","DOIUrl":"10.1007/s12017-026-08911-2","url":null,"abstract":"","PeriodicalId":19304,"journal":{"name":"NeuroMolecular Medicine","volume":"28 1","pages":""},"PeriodicalIF":3.9,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12963242/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147355032","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Retraction Note: 5‑N‑ethyl Carboxamidoadenosine Stimulates Adenosine‑2b Receptor‑Mediated Mitogen‑Activated Protein Kinase Pathway to Improve Brain Mitochondrial Function in Amyloid Beta‑Induced Cognitive Deficit Mice.","authors":"Bhupesh Chandra Semwal, Debapriya Garabadu","doi":"10.1007/s12017-026-08907-y","DOIUrl":"https://doi.org/10.1007/s12017-026-08907-y","url":null,"abstract":"","PeriodicalId":19304,"journal":{"name":"NeuroMolecular Medicine","volume":"28 1","pages":"10"},"PeriodicalIF":3.9,"publicationDate":"2026-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146227394","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Montelukast Modulates MPTP-induced Ferroptosis and Neuroinflammation Linked To the GPX4/ACSL4/5-LOX Pathway.","authors":"Yu Jin Jung, Hyunsu Choi, Seon-Min Lee, Eungseok Oh","doi":"10.1007/s12017-025-08895-5","DOIUrl":"https://doi.org/10.1007/s12017-025-08895-5","url":null,"abstract":"<p><p>Ferroptosis, an iron-dependent form of regulated cell death, has been increasingly linked to neurodegeneration in Parkinson's disease (PD). The lipid-peroxidizing enzyme 5-lipoxygenase (5-LOX) contributes to ferroptotic stress, while montelukast, a leukotriene receptor antagonist widely used for asthma, indirectly interferes with this pathway. Here, we investigated whether montelukast protects against dopaminergic injury in a mouse model of PD induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Mice were evaluated for behavioral deficits and underwent histological and biochemical analyses to assess iron burden, oxidative stress, ferroptosis markers, and neuroinflammation. Montelukast administration alleviated MPTP-induced motor dysfunction, preserved tyrosine hydroxylase-positive neurons, and reduced α-synuclein accumulation. Treatment also decreased iron deposition and malondialdehyde production while restoring glutathione and superoxide dismutase activity. At the molecular level, montelukast upregulated xCT/GPX4 while downregulating ACSL4/5-LOX, indicating suppression of ferroptosis. Moreover, montelukast attenuated microglial activation and pro-inflammatory cytokine expression. Collectively, our results suggest that prophylactic administration of montelukast mitigates dopaminergic neurodegeneration by modulating markers of ferroptosis and inflammatory signaling. These findings indicate the GPX4/ACSL4/5-LOX axis as a potential neuroprotective target for PD.</p>","PeriodicalId":19304,"journal":{"name":"NeuroMolecular Medicine","volume":"28 1","pages":"11"},"PeriodicalIF":3.9,"publicationDate":"2026-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146227380","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Searching for New Possible Peripheral Biomarkers of Cognitive Decline in Down Syndrome: The Role of IL-18 Pathway and its Interaction with TGF-β1 and TNF-α.","authors":"Margherita Grasso, Annamaria Fidilio, Francesca L'Episcopo, Marilena Recupero, Concetta Barone, Marta Lovino, Silvia Alboni, Maria Giulia Bacalini, Giuseppe Caruso, Donatella Greco, Serafino Buono, Rafael De La Torre, Fabio Tascedda, Johanna Mc Blom, Cristina Benatti, Filippo Caraci","doi":"10.1007/s12017-025-08901-w","DOIUrl":"https://doi.org/10.1007/s12017-025-08901-w","url":null,"abstract":"<p><p>Down syndrome (DS) represents one of the most common genetic disorders attributable to a partial or complete trisomy of chromosome 21 that affects about 1 in 700 individuals at birth. The diagnosis of Alzheimer's Disease (AD)-correlated cognitive decline in this population requires new approaches and new biomarkers that comprehensively assess health status and early cognitive decline. In this observational study, we explored for the first time the relation of IL-18, a cytokine member of IL-1 family involved in both innate and acquired immune responses, with DS associated cognitive decline. We observed that plasma total IL-18, in subjects with DS over 35 with and without AD-related cognitive decline, and plasma concentrations of its binding protein in subjects with DS (19-35 years) were correlated with lower plasma concentrations of Transforming Growth Factor (TGF-β1), which are linked to an increased rate of cognitive decline in adults with DS. In addition, we found a significant association between low baseline concentrations of Free IL-18, the active form of the cytokine, and an increased rate of cognitive decline at 12 months, calculated as delta of the Test for Severe Impairment (dTSI), in individuals with DS (19-35 years). Finally, we demonstrated a reduction of Free IL-18/TNF-α ratio, considered as a new possible double biomarker, in both young and older adult DS subjects without AD-related cognitive decline (area under the receiver operating curve (AUC) was 0.82 and 0.71, respectively), suggesting the advantage of the composite biomarkers in the discrimination of patients from healthy people over single biomarkers.</p>","PeriodicalId":19304,"journal":{"name":"NeuroMolecular Medicine","volume":"28 1","pages":"12"},"PeriodicalIF":3.9,"publicationDate":"2026-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146227470","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pterostilbene Orchestrates Synaptic Remodeling and Mitochondrial Functional Reconstitution to Attenuate Ischemic Vascular Dementia.","authors":"Bhaskar Jyoti Dutta, Vishal Shivaji Patil, Sanjiv Singh","doi":"10.1007/s12017-026-08909-w","DOIUrl":"https://doi.org/10.1007/s12017-026-08909-w","url":null,"abstract":"<p><p>Vascular dementia (VaD), a major contributor to cognitive decline, arises primarily from impaired regulation of cerebral circulation. Pterostilbene (PTE), a natural stilbene, exhibits potent neuroprotective properties, including antioxidative, anti-apoptotic, and cognition-enhancing effects; however, the molecular basis of its protective action in VaD remains poorly defined. Here, we integrated network pharmacology with in-vitro and in-vivo validation to delineate the mechanistic underpinnings of PTE. An ischemic injury model was established in SH-SY5Y cells using oxygen-glucose deprivation/reoxygenation (OGD/R), while VaD was induced in rats by bilateral common carotid artery occlusion. Cognitive function was assessed by behavioural paradigms, and neuronal integrity, vascular architecture, mitochondrial function, respiratory complex activities, and synaptic plasticity via the cAMP/PKA/CREB signalling cascade were evaluated using histological, biochemical, and molecular assays. Network pharmacology identified the cAMP pathway as a principal mediator of PTE activity. In ischemia injured SH-SY5Y cells, PTE improved viability, reduced oxidative stress, stabilized mitochondrial membrane potential, and elevated ATP production. In VaD rats, PTE enhanced spatial learning and memory, preserved cortical and hippocampal structures, and promoted mitochondrial health, evidenced by upregulation of PGC-1α and TFAM, restoration of respiratory complex activities, and preservation of mitochondrial ultrastructure. PTE also increased expression of synaptic proteins (PSD95, Synaptophysin). Consistently across both models, PTE activated the cAMP/PKA/CREB signalling axis. Collectively, these findings demonstrate that PTE mitigates ischemia-induced cognitive impairment by reversing mitochondrial dysfunction while sustaining synaptic plasticity through cAMP/PKA/CREB activation, highlighting its translational potential as a therapeutic candidate for VaD.</p>","PeriodicalId":19304,"journal":{"name":"NeuroMolecular Medicine","volume":"28 1","pages":"13"},"PeriodicalIF":3.9,"publicationDate":"2026-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146227375","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Simvastatin Ameliorates Lipid Metabolism-Mediated Endothelial Inflammation and Tight Junction Impairment in Chronic Cerebral Hypoperfusion.","authors":"Ruihua Sun, Wanyue Li, Xiaoyi Ji, Wenjian Hu, Ying Zhao, Yaru Lu, Junkui Shang, Xiaodi Hao, Jiewen Zhang","doi":"10.1007/s12017-026-08910-3","DOIUrl":"https://doi.org/10.1007/s12017-026-08910-3","url":null,"abstract":"<p><p>Chronic cerebral hypoperfusion (CCH) is a key pathological hallmark observable in multiple subtypes of cerebral small vessel disease (CSVD). This condition causes both structural and functional changes within the brain's vascular system, and is particularly damaging to brain microvascular endothelial cells (BMECs). The exact molecular mechanisms underlying BMEC impairment in CCH remain insufficiently defined despite their clinical importance. Emerging evidence indicates that disturbances in intracellular lipid metabolism might contribute substantially to promoting endothelial inflammation and functional deficits. This study aims to investigate whether aberrant lipid metabolism contributes to endothelial inflammation and tight junction (TJ) dysfunction in BMECs under the condition of CCH, and to assess the therapeutic potential of intervention with simvastatin. A rat model of chronic CSVD was created via permanent bilateral ligation of the common carotid arteries (2VO) in animal subjects. Samples of cortical microvasculature were collected at predefined intervals for transcriptome profiling. Assessments of lipid metabolism, inflammation-related factors, and TJ protein levels were conducted in both in vivo and after induction of hypoxia and administration of simvastatin. At 14d post-2VO, mRNA expression of TJ proteins including occludin (Ocln), claudin-5 (Cldn5), and zonula occludens-1 (Zo-1) was significantly downregulated in BMECs compared to sham controls. Simultaneously, there was a notable buildup of lipid droplets, rise in cholesterol levels, and upregulation of pro-inflammatory indicators including VCAM1, TNF-α, and ICAM1. Simvastatin administration effectively reduced lipid buildup, suppressed inflammation, and restored TJ integrity. Dysregulated lipid metabolism and heightened inflammatory responses contribute to TJ disruption in BMECs with CCH. Simvastatin therapy mitigates lipid accumulation, dampens inflammation, and improves TJ function in BMECs with CCH.</p>","PeriodicalId":19304,"journal":{"name":"NeuroMolecular Medicine","volume":"28 1","pages":"9"},"PeriodicalIF":3.9,"publicationDate":"2026-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146132750","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phloretin as a Multitarget Neuroprotective Agent: Mechanistic Insights into the Modulation of Oxidative Stress, Inflammation, and Apoptosis.","authors":"Parmila Kumari, Lovedeep Singh","doi":"10.1007/s12017-026-08908-x","DOIUrl":"https://doi.org/10.1007/s12017-026-08908-x","url":null,"abstract":"<p><p>Neurodegenerative diseases impose a substantial and growing global burden, affecting millions worldwide and leading to high medical, social, and economic costs. These are characterized by progressive neuronal dysfunction and loss, leading to cognitive, motor, and behavioral impairments. Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and Huntington's disease are driven by intertwined mechanisms of oxidative stress, neuroinflammation, protein aggregation, and neuronal apoptosis. Activation of the TLR-2/NF-κB axis promotes neuroinflammation and pyroptotic cell death through excessive production of pro-inflammatory cytokines, contributing to neuronal damage. Dysregulation of the TLR-2/Akt/mTOR pathway impairs autophagy, leading to defective clearance and accumulation of α-synuclein, a central event in synucleinopathies. Moreover, compromised Nrf2-mediated antioxidant signaling weakens cellular redox homeostasis and anti-apoptotic defenses, thereby linking redox imbalance to caspase-dependent neuronal apoptosis. Given the complex and multifactorial nature of neurodegenerative diseases, there is a pressing need for multitarget agents. Phloretin is a natural dihydrochalcone predominantly found in apples, pears, and strawberries. It exhibits broad pharmacological activities, including antioxidant, anti-inflammatory, anti-apoptotic, and neuroprotective effects, making it a promising multitarget phytochemical for neurodegenerative conditions. Phloretin mediates its neuroprotective properties through the modulation of several mediators, including Aβ, TLR-2, NF-κB, COX, iNOS, PPARγ, Nrf2, beclin-1, Bax, Bcl-2, caspases, PI3K/Akt, mTOR, pro-inflammatory cytokines, and antioxidant enzymes, among others. Despite compelling preclinical evidence, critical gaps remain regarding phloretin's effects on inflammasome initiation, ER stress responses, mitophagy, neurotrophic signaling, and, importantly, its clinical safety and efficacy, underscoring the need for integrated mechanistic studies and well-designed clinical trials.</p>","PeriodicalId":19304,"journal":{"name":"NeuroMolecular Medicine","volume":"28 1","pages":"8"},"PeriodicalIF":3.9,"publicationDate":"2026-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146119510","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Spinal Cord Involvement in Patients with Adult-Onset Multiple Acyl-CoA Dehydrogenase Deficiency.","authors":"Wei Wang, Min Zhu, Yunwen Zhong, Lu Wang, Yusen Qiu, Kaiyan Jiang, Ying Xiong, Pengcheng Huang, Xin Fang, Meihong Zhou, Dandan Tan, Daojun Hong","doi":"10.1007/s12017-025-08904-7","DOIUrl":"https://doi.org/10.1007/s12017-025-08904-7","url":null,"abstract":"<p><p>Riboflavin responsive multiple acyl-CoA dehydrogenase deficiency (RR-MADD) is an inherited metabolic disorder which is good responsive to riboflavin treatment. The phenotypic spectrum of adult-onset RR-MADD is highly heterogeneous. In this study, we described three patients with adult-onset RR-MADD presented with muscle weakness and spinal cord involvement. These three patients presented with adult-onset limb weakness, dyspnea, along with sensory levels changes (patient 1 below T2 level, patient 2 below T6 level, and patient 3 below T12 level, respectively). All patients displayed elevated acylcarnitine and urinary organic acids. Muscle biopsies in patient 1 and patient 2 revealed the presence of lipid vacuoles and COX-negative fibers. Genetic analysis identified ETFDH mutation (c.524G > A (p.R175H)) in patient 1, and a compound heterozygous ETFDH mutation (c.34G > C (p.A12P)/c.736G > A (p.E246K)) in patient 2. Spinal-cord MRI excluded structural lesions, whereas muscle MRI indicated fatty infiltration. Short-term riboflavin treatment proved effective in alleviating muscle weakness, while long-term administration of riboflavin, coenzyme Q10, and vitamin B12 demonstrated efficacy in alleviating spinal cord involvement. Inconclusion, our findings suggest that spinal cord involvement may manifest in certain patients with adult-onset RR-MADD, which expand the neurological spectrum of adult-onset RR-MADD.</p>","PeriodicalId":19304,"journal":{"name":"NeuroMolecular Medicine","volume":"28 1","pages":"6"},"PeriodicalIF":3.9,"publicationDate":"2026-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146086552","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}