NeuroMolecular Medicine最新文献

{"title":"Inflammatory Markers and their Relationship with Cognitive Function in Alzheimer's Disease and Mild Cognitive Impairment. Systematic Review and Meta-Analysis.","authors":"Maria Fernanda Serna, Mildrey Mosquera, Herney Andrés García-Perdomo","doi":"10.1007/s12017-025-08866-w","DOIUrl":"https://doi.org/10.1007/s12017-025-08866-w","url":null,"abstract":"<p><p>This study estimates the association between blood levels of inflammatory markers and cognitive function in adults with Alzheimer's disease or mild cognitive impairment. A systematic review and meta-analysis were conducted to synthesize data from studies examining the relationship between blood levels of inflammatory markers and cognitive function in adults with Alzheimer's disease or mild cognitive impairment. The search strategy was applied to the Medline database through MEDLINE (OVID), WEB OF SCIENCE, SCOPUS, LILACS, and the Cochrane Central Register of Controlled Trials (CENTRAL). Studies were selected based on predefined criteria. We included 84 studies in the qualitative synthesis, with 75 incorporated into the meta-analysis. In blood samples, subjects with Alzheimer's disease showed significantly higher concentrations of IL-1β (mean difference 0.46 [95% CI: 0.35, 0.58]), IL-6 (3.41 [3.05, 3.78]), MCP-1 (26.20 [14.57, 37.82]), and TNF-α (6.68 [5.97, 7.39]), along with lower concentrations of IL-8 (- 1.46 [- 1.85, - 1.08]) and IL-10 (- 3.20 [- 4.21, - 2.20]). This systematic review and meta-analysis demonstrate significant alterations in inflammatory marker concentrations in blood samples of individuals with Alzheimer's disease and mild cognitive impairment. Elevated levels of IL-1β, IL-6, MCP-1, and TNF-α, alongside reduced IL-8 and IL-10 levels, suggest a robust inflammatory response associated with Alzheimer's disease.</p>","PeriodicalId":19304,"journal":{"name":"NeuroMolecular Medicine","volume":"27 1","pages":"53"},"PeriodicalIF":3.3,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144708318","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":"Ca²⁺-Affinitive and Non-Ca²⁺-Affinitive Synaptotagmins in Human Pan-cancer.","authors":"Xuanang Wu, Bo Gao, Kun Xiao, Nimra Saleem","doi":"10.1007/s12017-025-08873-x","DOIUrl":"https://doi.org/10.1007/s12017-025-08873-x","url":null,"abstract":"<p><p>Synaptotagmins (Syts) are a family of crucial Ca²⁺ sensors for cellular secretions, while half of the Syt isoforms are evolutionarily non-Ca²⁺-affinitive, which are less studied but associated with several neuro-system diseases. Some Syt isoforms exhibited importance in specific cancer types, but a comprehensive study of all Syts in pan-cancer is lacking. Here, using informatics tools and proteome/transcriptome databases, the expression, phosphorylation, CpG methylation profiles, and the correlation with genome heterogeneity, tumor stemness, and immune infiltration of all human Syts are analyzed in human pan-cancer, resulting in significant associations of each Syt in various types of cancer, including pathological stage and prognosis. Most Syts exhibit noteworthy expression level changes in GBM/LGG and PCPG, and Syt11 has a strong association with immune infiltration. The Ca²⁺-affinitive and non-Ca²⁺-affinitive Syt groups show opposite changes in both expression and methylation levels in an overview scale suggesting different mechanisms of them in cancers. Detection of similar expression genes suggests that Ca²⁺-affinitive Syts may participate in the RNA-splicing process, while non-Ca²⁺-affinitive Syts are involved in NF-κB signaling and immune regulation. This study uncovers the clinical potential of each Syt isoform and discusses clues to their roles, such as Ca²⁺ sensitivity and immune regulation, in tumor progression. The overall data are informative for future refining and mining.</p>","PeriodicalId":19304,"journal":{"name":"NeuroMolecular Medicine","volume":"27 1","pages":"52"},"PeriodicalIF":3.3,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144659725","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":"Equol as a Multitarget Agent Against Neurodegeneration: Mechanistic Insights into Its Molecular Modulation.","authors":"Nushrat Jahan, Lovedeep Singh, Jyoti Sharma","doi":"10.1007/s12017-025-08875-9","DOIUrl":"https://doi.org/10.1007/s12017-025-08875-9","url":null,"abstract":"<p><p>Neurodegenerative diseases consist of a group of progressive disorders characterized by the gradual decline in the structure or function of neurons, which ultimately results in neuronal death. The occurrence and societal effects of these disorders have been consistently rising, presenting considerable public health challenges globally. Multiple interconnected pathways, including oxidative stress, neuroinflammation, nitrosative stress, and apoptosis, drive their progression. NOX-induced ROS disrupts neuronal function, impairs mitochondrial activity, and triggers lipid peroxidation, contributing to neuronal death. Activation of the TLR-4/MAPK/NF-κB pathway triggers neuroinflammation and NLRP3 inflammasome activation. This inflammasome-driven inflammation accelerates neuronal injury and death. Moreover, reduced estrogen receptor expression weakens neuronal defenses, impairing synaptic function, thereby worsening neurodegeneration. Neurodegenerative diseases continue to be without a cure, as existing treatments focus on alleviating symptoms and modifying the disease. Due to their intricate and multifactorial pathophysiology, there is a pressing need for agents capable of targeting multiple pathological mechanisms to effectively combat these disorders. Various phytomolecules have shown promise in tackling different neurodegenerative diseases by modulating key molecular targets. Equol (4',7-isoflavandiol) is a metabolite of daidzein, a soy isoflavone present in soybeans and various other plant sources. Equol has shown significant promise in combating neurodegeneration by modulating mediators involved in oxidative stress, neuroinflammation, nitrosative stress, and apoptosis. Key signaling molecules influenced by equol include TLR-4, MAPKs, NLRP3 inflammasome, ROS, and inflammatory mediators, among others. Considering equol's ability to modulate these signaling mediators, this review explores the mechanistic pathways through which equol confers neuroprotection.</p>","PeriodicalId":19304,"journal":{"name":"NeuroMolecular Medicine","volume":"27 1","pages":"51"},"PeriodicalIF":3.3,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144642968","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":"Dysbiosis and Neurodegeneration in ALS: Unraveling the Gut-Brain Axis.","authors":"Vivek Kumar Sharma","doi":"10.1007/s12017-025-08870-0","DOIUrl":"https://doi.org/10.1007/s12017-025-08870-0","url":null,"abstract":"<p><p>Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, is a neurodegenerative disorder marked by the progressive degeneration of motor neurons in the brain and spinal cord. Despite decades of research, ALS remains incurable, diagnostically elusive, and is accompanied by rapid clinical decline, morbidity, and mortality. Its pathophysiology involves a complex interplay of genetic mutations (SOD1, C9/f72), environmental triggers, oxidative stress, neuroinflammation, and the accumulation of misfolded proteins, such as TDP-43 and SOD1. These factors disrupt cellular homeostasis aggravates excitotoxicity and neuronal death. Existing treatments, such as riluzole (a glutamate release modulator) and edaravone (a free radical scavenger), offer limited benefits, modestly prolonging survival or slowing functional decline without halting progression. Investigational approaches include antisense oligonucleotides targeting mutant SOD1 or C9orf72 genes, stem cell-based motor neuron replacement, and biomarker discovery to enable earlier diagnosis and progression monitoring. ALS patients frequently exhibit gastrointestinal (GI) symptoms, including dysphagia, sialorrhea, constipation, delayed gastric emptying, and pancreatic/parotid deficiencies. These observations underscore a close association between GI dysfunction and ALS pathogenesis. Also, recent studies implicate the gut-brain-microbiota axis in disease evolution, with microbial metabolites influencing neuroimmune interactions, synaptic plasticity, myelination, and skeletal muscle function. These studies indicate that dysbiosis-an imbalance in gut microbiota-may have a crucial role in ALS progression by impairing intestinal barrier integrity, promoting endotoxemia, and driving systemic inflammation. Conversely, ALS progression itself worsens dysbiosis, creating a vicious cycle of neuroinflammation and neurodegeneration. Preclinical and clinical evidence suggests that interventions targeting gut microbiota-such as prebiotics, probiotics, antibiotics, or phage therapy-could alleviate symptoms and slow disease progression and specific probiotic strains have also shown promise in reducing oxidative stress and inflammation in animal models. These findings highlight the urgent need to elucidate the functional role of gut microbiota in ALS to unlock novel diagnostic and therapeutic avenues. This review synthesizes current knowledge on the pathophysiology of ALS, with a focus on the emerging role of the gut-brain-microbiota axis. It highlights how dysbiosis influences diverse disease markers and neurodegenerative mechanisms, offering insights into potential therapeutic strategies and identifying key research gaps and future directions.</p>","PeriodicalId":19304,"journal":{"name":"NeuroMolecular Medicine","volume":"27 1","pages":"50"},"PeriodicalIF":3.3,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144554038","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":"Scopoletin Attenuates Reserpine-Induced Pain-Depression Dyad in Mice via Modulation of Inflammation, Oxidative Stress, and Monoaminergic Pathways.","authors":"Esam Qnais, Omar Gammoh, Yousra Bsieso, Alaa A A Aljabali, Abdelrahim Alqudah, Zaid Alawneh, Hamzah Hajaj, Badriyah S Alotaibi","doi":"10.1007/s12017-025-08869-7","DOIUrl":"https://doi.org/10.1007/s12017-025-08869-7","url":null,"abstract":"<p><p>Pain and depression frequently are comorbid and have common mechanisms such as monoamine depletion, inflammation, and oxidative stress. Hence, this study aimed to investigate the effects of bioactive coumarin on reserpine induced pain-depression dyad in mice. Mechanical allodynia, depressive-like behavior, and cognitive deficits were induced by reserpine (0.5 mg/kg, subcutaneously, once daily on days 1-3) in male BALB/c mice. Scopoletin (50 mg/kg, p.o.) or gabapentin (10 mg/kg, p.o.) was given twice daily (at 9:00 am and 5:00 pm) for 5 days. For days 1-3, the initial daily dose of scopoletin or gabapentin was given 30 min before reserpine injection, with the second dose at the evening. Control animals, which received vehicle, were given 0.1% CMC. Behavioural tests (Electronic von Frey (eVF) test, Pressure Application Measurement (PAM) test) (Forced Swim Test (FST) and Morris Water Maze (MWM) test) were performed on day 4 and 6, and tissue collection was conducted on day 6 for biochemical analyses (cytokines (TNF-α and IL-1β), neurotransmitters (Serotonin, Norepinephrine, and Glutamate), MAO-A activity, GSH, TBARS). Paw withdrawal thresholds (eVF day 4: F(3,20) = 28.75, p < 0.001; PAM: F(3,20) = 35.17, p < 0.001) were markedly diminished and immobility time in FST (F(3,20) = 29.11, p < 0.001) was notably prolonged by reserpine. Moreover, it impaired the spatial memory (MWM: F(3,20) = 30.56, p < 0.001), and increased the serum TNF-α and IL-1β (F(3,20) = 24.32 and 18.50, respectively; p < 0.01), the brain MAO-A activity (F(3,20) = 16.83, p < 0.01), glutamate and TBARS (F(3,20) = 25.11, p < 0.001; F(3,20) = 19.76, p < 0.01), and decreased the brain serotonin, norepinephrine and GSH (p < 0.01-0.001). Supplementation with scopoletin markedly retarded deficits in behavior (eVF and PAL, p < 0.001; FST, p < 0.001; MWM, p < 0.001) and biochemistry (reduction of UG [TNF-α, IL-1β], MAO-A activity and glutamate level along with restoration of monoamine and antioxidant status, p < 0.05-0.001). Scopoletin is a promising candidate drug for comorbid pain and depression due to its significant counteracting effects on reserpine-induced behavioral and biochemical alterations.</p>","PeriodicalId":19304,"journal":{"name":"NeuroMolecular Medicine","volume":"27 1","pages":"49"},"PeriodicalIF":3.3,"publicationDate":"2025-06-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144529067","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":"Knockdown of RUNX2 Attenuated A1 Astrocyte Overactivation, Brain Injury, and Cerebral Edema During Ischemic Stroke.","authors":"Zhibing Ai, Wei Huang, Wei Hu, Ran An, Gongwen Lei, Wen Gu, Xiaoqin Peng, Yong Liu","doi":"10.1007/s12017-025-08868-8","DOIUrl":"https://doi.org/10.1007/s12017-025-08868-8","url":null,"abstract":"<p><p>Although researchers began to unravel the potential significance of Runt-related transcription factor 2 (RUNX2) in some of neurological diseases, the role of RUNX2 in ischemic stroke remained unclear. Blood samples and clinical information were collected from stroke patients and control subjects. Besides, middle cerebral artery occlusion (MCAO) mice model and astrocytes oxygen-glucose deprivation/reperfusion (OGD/R) were established to simulate the pathological process of stroke in vivo and in vitro. Loss-of-function assay was used to assess the effect of RUNX2 on astrocytes function. HE staining and Nissl staining were used to examine the histopathological changes of brain tissues in mice. TTC staining was used to measure the cerebral infarct volume in mice. Morri's water maze test, the corner turn test, and the balance beam test were performed to evaluate neurobehavioral performances of mice. The results showed that the expression and serum content of RUNX2 were upregulated in stroke patients and mice. Knocking-down RUNX2 inhibited OGD/R-induced increases of proliferation and migration, while reversed the decrease of apoptosis in astrocytes. Moreover, RUNX2 knockdown also suppressed the inflammatory response in OGD/R-treated astrocytes and promoted the conversion of the reactive astrocyte phenotype from A1 to A2. The serum mRNA expression and level of RUNX2 were both notably increased in patients with cerebral edema. RUNX2 knockdown weakened cerebral edema and swelling of astrocytes. The results of HE staining and Nissl staining suggested that RUNX2 knockdown notably improved neuronal damage in the brain tissues of MCAO mice and also improved the injured performance of MCAO stroke mice in the behavioral test. In conclusion, RUNX2 expression was upregulated during the pathological progression of ischemic stroke. Furthermore, the knockdown of RUNX2 alleviated OGD/R-induced astrocytes activation and swelling, while inhibiting the polarization and inflammatory response in astrocytes. More importantly, RUNX2 interference also improved neuronal damage, cerebral edema, and neurobehavioral performances of MCAO mice.</p>","PeriodicalId":19304,"journal":{"name":"NeuroMolecular Medicine","volume":"27 1","pages":"48"},"PeriodicalIF":3.3,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144507131","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":"Xanthoxylin Regulating the Inflammatory Microenvironment After Spinal Cord Injury Through Inhibition of the NF-κB Signaling Pathway.","authors":"Zihao Fan, Lei Ye, Shijie Wang, Zhengming Zhu, Chaoqun Wu, Chaofan Wu, Lingchao Kong, Rende Ning","doi":"10.1007/s12017-025-08863-z","DOIUrl":"10.1007/s12017-025-08863-z","url":null,"abstract":"<p><p>Spinal Cord Injury (SCI) is a severe disorder of the central nervous system, typically caused by trauma or disease, which significantly impacts the quality of life of affected individuals. Secondary inflammation following spinal cord injury is a critical factor influencing prognosis, making the exploration of the inflammatory microenvironment crucial for the treatment of SCI. Xanthoxylin, a small organic molecule extracted from plants, has demonstrated notable anti-inflammatory effects. To investigate the role of Xanthoxylin in spinal cord injury, we initially employed Hoechst staining and flow cytometry, revealing that Xanthoxylin reduces neuronal apoptosis. Subsequently, through Western blot, immunofluorescence, and qPCR, we discovered that Xanthoxylin promotes the polarization of microglia from the M1 inflammatory phenotype to the M2 anti-inflammatory phenotype. Furthermore, transcriptome sequencing identified differential expression in the NF-κB pathway, which was corroborated by Western blot analysis. Finally, animal experiments were conducted to further validate the therapeutic effects of Xanthoxylin on spinal cord injury in mice. These results suggest that Xanthoxylin has a significant therapeutic effect on SCI in mice. Overall, our study is the first to demonstrate the therapeutic effect of Xanthoxylin on SCI and provides a scientific exploration of its underlying mechanisms, offering new directions for pharmacological treatment of spinal cord injury.</p>","PeriodicalId":19304,"journal":{"name":"NeuroMolecular Medicine","volume":"27 1","pages":"47"},"PeriodicalIF":3.3,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12179010/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144326363","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":"Altered Microglial Plasticity in the Periaqueductal Grey of Pre-Symptomatic Mecp2-Heterozygous Mice Following Early-Life Stress.","authors":"Maria Abellán-Álvaro, Lidia Primo-Hernando, Elena Martínez-Rodríguez, Enrique Lanuza, Mónica Santos, Carmen Agustín-Pavón, Jose V Torres-Pérez","doi":"10.1007/s12017-025-08867-9","DOIUrl":"10.1007/s12017-025-08867-9","url":null,"abstract":"<p><p>Rett syndrome (RTT), a severe neurodevelopmental disorder primarily affecting girls, is commonly caused by MECP2 loss-of-function mutations. Key symptoms include motor impairments, typical hand stereotypies and intellectual disability. Moreover, although not thoroughly studied, anxiety, heightened stress sensitivity, and aberrant pain perception are also an important component of the RTT phenotype. Emerging evidence suggests that early-life stress (ELS) worsens Mecp2-related phenotypic alterations in mice. Microglia, the resident immune cells within the central nervous system, play a critical role in RTT pathophysiology, yet the combined impact of ELS and Mecp2 deficiency on microglia has not been studied. Previously, we observed reduced activation of the periaqueductal grey (PAG, a cerebral structure involved in pain modulation, autonomic control, and defensive behaviours) in Mecp2-heterozygous (Mecp2-het) mice after thermal stimulation. Here, we investigated the impact of ELS on microglia morphology in the PAG under Mecp2 deficiency. To this end, we analysed microglia in the PAG of presymptomatic Mecp2-het mice previously subjected to maternal separation (MS) as a model of ELS, alongside corresponding control animals. Brain sections were immunolabelled for IBA1, a pan-microglial marker. Microglial cells within the PAG were evaluated for expression levels, morphological characteristics, and fractal properties. While global PAG analyses showed minimal differences, subdivision-specific analyses revealed significant microglial alterations. These findings suggest that ELS exacerbates Mecp2-related neurodevelopmental deficits, impairing microglia in a region-specific manner. Our data points to a microglial failure to morphologically adapt, rather than overt structural loss, in the PAG that may underlie some of the neurological dysfunctions observed in RTT.</p>","PeriodicalId":19304,"journal":{"name":"NeuroMolecular Medicine","volume":"27 1","pages":"46"},"PeriodicalIF":3.3,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12174278/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144317531","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":"Memory-Enhancing Effects of Dauricine in Swiss Mice: Possible Molecular Interventions Through In Vivo and In Silico Studies.","authors":"Md Showkot Akbor, Md Sakib Al Hasan, Mst Farjanamul Haque, Zakir Husain, Md Tahajul Islam, Md Samim Hossen, Md Shadin, Shoyaeb Ahammed, Noshin Tasnim Yana, Siddique Akber Ansari, Irfan Aamer Ansari, Muhammad Torequl Islam","doi":"10.1007/s12017-025-08839-z","DOIUrl":"https://doi.org/10.1007/s12017-025-08839-z","url":null,"abstract":"<p><p>The bisbenzylisoquinoline alkaloid dauricine (DAU) is known for its neuroprotective effects in animals. This study investigates the memory-enhancing effects of DAU in Swiss albino mice using both in vivo and in silico approaches, focusing on its interaction with the D2 dopamine (DOP) receptor. Behavioral tests, including marble burying, dust removal, and trained swimming, were used to assess cognitive performance, anxiety, and motor coordination. Molecular docking studies revealed that DAU binds strongly to the D2 DOP receptor (6CM4 protein), with a binding affinity of - 7.9 kcal/mol, forming significant hydrogen and hydrophobic bonds. Additionally, the pharmacokinetics and toxicity profiles of DAU were also evaluated. In vivo results showed that DAU improved behavioral performance in a dose-dependent manner, with the DAU-10 group showing significant (p < 0.05) enhancement compared to the control and standard groups. The DAU-10 + DOP-22 combination group also showed remarkable results compared to the standard alone. Pharmacokinetics and toxicity profiles were also assessed, revealing favorable properties but some concerns regarding mutagenicity and immunotoxicity. These findings suggest that DAU, especially when combined with D2 DOP receptor agonists, holds significant potential for memory enhancement and warrants further investigation.</p>","PeriodicalId":19304,"journal":{"name":"NeuroMolecular Medicine","volume":"27 1","pages":"45"},"PeriodicalIF":3.3,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144226082","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":"Tau from SPAM Transgenic Mice Exhibit Potent Strain-Specific Prion-Like Seeding Properties Characteristic of Human Neurodegenerative Diseases.","authors":"Ethan D Smith, Giavanna Paterno, Brach M Bell, Kimberly-Marie M Gorion, Stefan Prokop, Benoit I Giasson","doi":"10.1007/s12017-025-08850-4","DOIUrl":"10.1007/s12017-025-08850-4","url":null,"abstract":"<p><p>Tauopathies, including Alzheimer's disease and frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17), are characterized by the aberrant aggregation of tau protein into neurofibrillary tangles. Despite extensive studies on tau aggregation, the mechanisms of tau misfolding and propagation remain incompletely understood. In this study, we utilize the SPAM (S320F/P301S) tau transgenic mouse model, which expresses 0N4R human tau with two FTDP-17 mutations, to investigate the biochemical properties and seeding potential of misfolded tau from these mice. Sarkosyl extraction and ultracentrifugation were employed to isolate detergent-insoluble tau aggregates (SPAM-tau) from aged SPAM mice. These aggregates were then tested for their prion-type seeding activity in an established HEK293T cell model comparing the induced aggregation of wild-type and mutant forms of human and murine tau. Our results show that SPAM-tau exhibits distinct and vigorous prion-like seeding properties, inducing the aggregation of human and murine tau homologues with the formation of amyloidogenic (Thioflavin S-positive) inclusions. Importantly, SPAM-tau aggregates can facilitate the prion-type misfolding of wild-type and mutant forms of human and mouse tau. We demonstrated that these induced tau aggregates are able to be further transmitted in passaging studies. Furthermore, SPAM-tau preferentially templated 4R tau isoforms, sharing strain-like seeding properties with insoluble tau derived from the brains of individuals with progressive supranuclear palsy (PSP-tau). In summary, these findings enhance our understanding of tau aggregation and propagation, suggesting that SPAM-tau may serve as a valuable tool for studying tauopathies and evaluating potential therapeutic strategies aimed at halting tau misfolding and propagation.</p>","PeriodicalId":19304,"journal":{"name":"NeuroMolecular Medicine","volume":"27 1","pages":"44"},"PeriodicalIF":3.3,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12125038/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144187456","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}