Molecular Neurobiology最新文献

{"title":"Overexpression of mGlu_7B in Mice: Implications for Neurodevelopmental Disorders.","authors":"Geanne A Freitas, Kelly Weiss, Vaishnavi Bavadekar, Sheryl Anne D Vermudez, Nicole M Fisher, Aditi Buch, Shalini Dogra, Zixiu Xiang, Rocco G Gogliotti, Colleen M Niswender","doi":"10.1007/s12035-025-05183-y","DOIUrl":"10.1007/s12035-025-05183-y","url":null,"abstract":"<p><p>Metabotropic glutamate receptor 7 (mGlu₇) is a G protein-coupled receptor (GPCR) involved in neurotransmitter release throughout the central nervous system (CNS). Low levels of the receptor are correlated with intellectual disability, autism, repetitive behaviors, and seizures in patients with neurodevelopmental disorders (NDDs), including the disease Rett syndrome. These findings suggest that increasing mGlu₇ activity may be of therapeutic benefit. In the current manuscript, we report the characterization of a novel transgenic mouse that overexpresses the human GRM7B splice variant at approximately fivefold higher levels compared to wild-type (WT) littermates. These animals exhibit a reciprocal decrease in expression of the mouse mGlu_7A splice isoform, suggesting feedback regulation of receptor expression. Previous studies from our lab and others have shown that mGlu₇ activation is permissive for long-term potentiation induction in the hippocampus and amygdala. Here, we identified subtle differences in agonist-modulated hippocampal field recordings in mice overexpressing mGlu_7B, but no changes in theta burst-induced long-term potentiation. Our lab previously characterized behavioral phenotypes in Grm7^-/- animals that were observed in other animal models of NDDs. Surprisingly, we find here that mGlu_7B-overexpressing mice exhibit similar phenotypes to previously reported studies in Grm7^-/- animals in repetitive behavior and cognition assays. Overall, these findings suggest that precise control of mGlu₇ may be required to avoid abnormal phenotypes.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":"14015-14031"},"PeriodicalIF":4.3,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12511187/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144601015","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Investigating the Role of Neutrophil Extracellular Traps as a Therapeutic Target in Traumatic Brain Injury: a Systematic Review and Meta-analysis.","authors":"Elliott Slough, Anna Pitt-Francis, Antonio Belli, Zubair Ahmed, Valentina Di Pietro, Andrew R Stevens","doi":"10.1007/s12035-025-05053-7","DOIUrl":"10.1007/s12035-025-05053-7","url":null,"abstract":"<p><p>Traumatic brain injury (TBI) is a leading cause of morbidity and mortality worldwide, with few treatment options to mitigate secondary injury. Neutrophil extracellular traps (NETs) may present a potential target for therapy. The systematic review objectives were to characterise NET formation as a feature following TBI; assess the effect of NET modulatory strategies on outcomes; and investigate the relative efficacy of NET modulatory methods. A systematic review was performed, with inclusion criteria of pre-clinical or clinical studies using any model or severity of TBI, and any investigation of the pathophysiological role of NETs and/or modulation of NETs for therapeutic benefit. Following search completion, 849 records were identified with 13 studies eligible for inclusion. All 13 studies characterised NET formation in blood and brain tissue from pre-clinical TBI models, whilst four studies also demonstrated NET formation in serum and brain tissue of TBI patients. Meta-analysis (where ≥ 3 studies reported outcomes) identified that NET modulation was associated with significant improvement of outcomes in preclinical studies, in both modified neurological severity score and latency to falls. No difference in efficacy was identified between NET modulatory methods after sub-group analysis. In addition, the overall risk of bias was judged as high in the included studies. This systematic review and meta-analysis demonstrated that NETs present a promising TBI therapeutic target for future clinical validation. However, the high bias limits this systematic review, and further high-quality studies are required to make definitive conclusions about NET utility as a viable therapeutic strategy in TBI.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":"14923-14946"},"PeriodicalIF":4.3,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12511129/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144128055","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Disrupted Lipid Metabolism Aggravates Ischemic Brain Injury: Targeting FDFT1 for Stroke Therapy.","authors":"Jing Yuan, Yu-Sha Liao, Tie-Chun Zhang, Shuang Liu, Min-Min Ruan, Ting-Ting Yang, Shi-Qi Sun, Long-Yao Xu, Xiao-Long Xie, Ling Zhao","doi":"10.1007/s12035-025-05217-5","DOIUrl":"10.1007/s12035-025-05217-5","url":null,"abstract":"<p><p>Lipid metabolism disorder has been established as a contributing factor to the exacerbation of ischemic stroke (IS) damage. Conditions such as metabolic dysfunction-associated steatotic liver disease (MASLD) and atherosclerosis are known to elevate the risk of IS. Therefore, elucidating the association between potential risk factors of IS and the pathogenesis of IS from the perspective of lipid regulation may provide new insight for the prevention and treatment. In our study, we obtained Gene Expression Omnibus Series (GSE) from NCBI (National Center for Biotechnology Information) GEO (Gene Expression Omnibus). Through the analysis of the datasets in MASLD and IS patients, we found that abnormal lipid metabolism is a potential pathway for stroke induced by MASLD as a risk factor. Furthermore, we established a middle cerebral artery occlusion-reperfusion (MCAO/R) model in mice, measured atherosclerotic lesions in ApoE-deficient mice, and performed RNA-seq analysis to identify differentially expressed genes (DEGs) following IS. Our findings indicate that the DEGs are associated with lipid metabolism signaling pathways and inflammatory response pathways. The ApoE mice exhibited more severe IS injury. edaravone, a free radical scavenger clinically used for acute ischemic stroke treatment, was employed here to investigate whether its neuroprotective pathways intersect with lipid metabolism regulation. We found that treatment with edaravone rectified metabolic disorders and mitigated IS damage. Furthermore, we observed that the expression of the hub gene Fdft1 was upregulated in both the brain and liver post-IS injury and significantly reduced following edaravone treatment. These findings suggest that lipid regulation is a promising avenue for IS therapy, and Fdft1 may emerge as a critical target for modulating lipid metabolism in the aftermath of IS.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":"14227-14244"},"PeriodicalIF":4.3,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12511267/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144659672","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of Fibroblast Growth Factors in Neurological Disorders: Insight into Therapeutic Approaches and Molecular Mechanisms.","authors":"Shubham Upadhayay, Divya Soni, Maanvi Dhureja, Pooja Temgire, Vishal Kumar, Richmond Arthur, Puneet Kumar","doi":"10.1007/s12035-025-04962-x","DOIUrl":"10.1007/s12035-025-04962-x","url":null,"abstract":"<p><p>In the last few decades, the incidence and progression of neurological disorders have consistently increased, which mainly occur due to environmental pollution, genetic abnormalities, and modern lifestyles. Several case reports suggested that these factors enhanced oxidative stress, mitochondrial dysfunction, inflammation, and apoptosis, leading to neurological disease. The pathophysiology of neurological disorders is still not understood, mainly due to the diversity within affected populations. Existing treatment options primarily provide symptomatic relief but frequently come with considerable side effects, including depression, anxiety, and restlessness. Fibroblast growth factors (FGFs) are key signalling molecules regulating various cellular functions, including cell proliferation, differentiation, electrical excitability, and injury responses. Hence, several investigations claimed a relationship between FGFs and neurological disorders, and their findings indicated that they could be used as therapeutic targets for neurological disorders. The FGFs are reported to activate various signalling pathways, including Ras/MAPK/PI3k/Akt, and downregulate the GSK-3β/NF-κB pathways responsible for anti-oxidant, anti-inflammatory, and anti-apoptotic effects. Therefore, researchers are interested in developing novel treatment options for neurological disorders. The emergence of unreported FGFs contributes to our understanding of their involvement in these conditions and encourages further exploration of innovative therapeutic approaches. All the data were obtained from published articles using PubMed, Web of Science, and Scopus databases using the search terms Fibroblast Growth Factor, PD, HD, AD, ALS, signalling pathways, and neurological disorders.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":"14367-14386"},"PeriodicalIF":4.3,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143993454","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":"Effect of High-Rate Repetitive Transcranial Magnetic Stimulation on Phonophobia and Brainstem Auditory Evoked Potential in Migraine.","authors":"Jayantee Kalita, Robin Bansal, Roopali Mahajan, Vishal Jha","doi":"10.1007/s12035-025-05190-z","DOIUrl":"10.1007/s12035-025-05190-z","url":null,"abstract":"<p><p>Phonophobia is a cardinal symptom in migraine, and migraineur may have impaired habituation of brainstem auditory evoked potential (BAEP). High-rate repetitive transcranial magnetic stimulation (rTMS) has been found effective in migraine, but its effect on brainstem excitability has not been evaluated. We report the effect of high-rate rTMS on ictal phonophobia, hearing threshold (HT), and BAEP as the biomarkers of impaired habituation in the patients with migraine. Forty-three migraineurs and 31 healthy controls were included. Their headache frequency and severity were noted, and ictal phonophobia was recorded on a 0-4 scale at baseline and one month after rTMS. Hearing threshold and three consecutive BAEP at 40 dBSL, 50 dBSL, and 60 dBSL were recorded at baseline and repeated after the 3rd session of rTMS. Peak latencies and amplitudes of BAEP waveforms were measured. Three sessions of 10 trains of 10 Hz rTMS were delivered over the left motor cortex corresponding to the hot spot of the abductor digiti minimi. Consecutive 3 tracings of BAEP at 40 dBSL, 50 dBSL, and 60 dBSL revealed increasing amplitudes of wave III and IV in migraineurs, which persisted even after rTMS. At 60 dBSL, wave III amplitude was higher in migraineurs compared to the control, and remained so after rTMS. The severity of phonophobia and HT, however, improved after rTMS. Migraineurs had improvement in phonophobia and HT following rTMS, which did not commensurate with the biomarkers of impaired habituation in BAEP. However, longer trains and multiple sessions of rTMS may be explored in further study.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":"14079-14088"},"PeriodicalIF":4.3,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144637665","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":"SOD1, A Crucial Protein for Neural Biochemistry: Dysfunction and Risk of Amyotrophic Lateral Sclerosis.","authors":"José Raphael Monteiro Neto, Gabriel Freitas de Souza, Vanessa Mattos Dos Santos, Luan de Holanda Paranhos, Gabriela Delaqua Ribeiro, Rayne Stfhany Silva Magalhães, Daniela Dias Queiroz, Elis Cristina Araujo Eleutherio","doi":"10.1007/s12035-025-05067-1","DOIUrl":"10.1007/s12035-025-05067-1","url":null,"abstract":"<p><p>Neurons are very susceptible to oxidative stress. They are the major consumers of oxygen in the brain, which is used to provide energy through oxidative phosphorylation, the major source of reactive oxygen species (ROS). In addition, compared to other tissues, neurons have lower levels of catalase and glutathione and increased susceptibility to lipid peroxidation due to the elevated levels of unsaturated fatty acids. These characteristics increasingly emphasize the antioxidant enzyme Cu/Zn superoxide dismutase 1 (SOD1) to maintain neuronal redox homeostasis. In the last decade, SOD1 gained additional roles which are also important to the metabolism of neurons. SOD1 controls the production of ROS by the electron transport chain, activates the expression of genes involved in the protection against oxidative stress, and regulates the shift from oxidative to fermentative metabolism involved in astrocyte-neuron metabolic cooperation. Furthermore, impaired interaction between the phosphatase calcineurin and SOD1 seems to result in TDP-43 hyperphosphorylation, the main proteinopathy found in amyotrophic lateral sclerosis (ALS) patients. However, this enzyme is ubiquitously expressed, mutated, and damaged forms of SOD1 cause disease in motor neurons. In this review, we discuss the pivotal functions of SOD1 in neuronal biochemistry and their implications for ALS.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":"14966-14986"},"PeriodicalIF":4.3,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144151260","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":"Activation of the C3 Complement Pathway in the Hippocampus Produces Anxiodepressive Effects in a Mouse Model of Inflammation Pain.","authors":"Aomei Zhang, Xinxin Zhang, Xiaohan Tang, Ming Liu, Jialing Xie, Suyun Li, Wenyu Cao, Huamao Zhou, Yang Xu","doi":"10.1007/s12035-025-05187-8","DOIUrl":"10.1007/s12035-025-05187-8","url":null,"abstract":"<p><p>The comorbidity of anxiety and depression frequently occurs in patients with inflammatory pain, which requires further investigation. Previous evidence supports a close link between Complement Component 3 (C3) and affective disorders; however, whether C3 is involved in inflammatory pain-induced anxiodepression remains unclear. Using a mouse inflammatory pain model with Complete Freund's Adjuvant (CFA), we observed that the animals exhibited significant anxiodepression-like behaviors and that the expression of hippocampal C3 was obviously increased three weeks after CFA injection. Microinjection of the AAV vector that downregulates C3 into the hippocampus alleviated anxiodepression-like behaviors. Moreover, we noted that knocking down hippocampal C3 partially alleviated pain behavior in CFA-treated mice. Mechanistically, we found that the benefit of knocking down the hippocampal C3 may be due to inhibition of its downstream C3aR-GSK3β signaling pathway and restoration of glia activation and inflammatory response to levels similar to those found under non-inflammatory conditions. Consequently, our work reveals the critical role of the hippocampal C3/C3aR-GSK3β signaling pathway in inflammatory pain-induced anxiodepression-like behaviors, suggesting that C3/C3aR-GSK3β signaling is a potential therapeutic target for inflammatory pain-induced mental health conditions.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":"14032-14049"},"PeriodicalIF":4.3,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144619089","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":"G-Protein-Coupled Receptor-Microtubule Interactions Regulate Neurite Development and Protect Against β-Amyloid Neurotoxicity.","authors":"Sneha Singh, Ujendra Kumar","doi":"10.1007/s12035-025-05179-8","DOIUrl":"10.1007/s12035-025-05179-8","url":null,"abstract":"<p><p>G-protein-coupled receptors (GPCRs) regulate multiple cellular functions, including neurite formation and maturation, processes often disrupted in neurodegenerative diseases. Like GPCRs, microtubule-associated proteins (MAPs, including MAP2 and Tuj1) and the synaptic vesicle protein synaptophysin are essential for neurite formation, maturation, and organization, which underpin brain development and cognitive function. Despite their importance, the functional crosstalk between GPCRs and MAPs, particularly in neurogenesis and pathological conditions such as Alzheimer's disease (AD), remains poorly understood. We show that somatostatin and dopamine receptors (SSTR and DR) are the structural anchors in developing neurites, enabling MAP recruitment and synaptic protein localization. Our findings reveal a cAMP-dependent interplay involving PTEN and ERK1/2, modulating neurite formation and MAPs organization. Notably, we show that β-amyloid (Aβ) disrupts the constitutive association of MAP2 and Tuj1, inducing an increase in intracellular cAMP levels, loss of neurite integrity, and impaired neuronal viability. The activation of SSTR and DR signaling restores neurite architecture and synaptic integrity via p-AKT activation and PTEN inhibition, highlighting a neuroprotective mechanism. Together, our results reveal a novel role of GPCRs in orchestrating interactions with MAPs to regulate neuronal maturation, neurite formation, and synaptic integrity. This study provides a new mechanistic rationale for therapeutic strategies aimed at preserving cognitive function in neurological disorders such as AD.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":"13878-13898"},"PeriodicalIF":4.3,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144540959","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 Influence of the Probiotics, Ketogenic Diets, and Gut Microbiota on Epilepsy and Epileptic Models: A Comprehensive Review.","authors":"Parmida Shirzadi, Parisa Farokh, Sima Osouli Meinagh, Ghazal Izadi-Jorshari, Bardia Hajikarimloo, Ghazaleh Mohammadi, Siavash Parvardeh, Marjan Nassiri-Asl","doi":"10.1007/s12035-025-04993-4","DOIUrl":"10.1007/s12035-025-04993-4","url":null,"abstract":"<p><p>About one-third of epilepsies are resistant to antiepileptic drugs; thus, uncovering new pathways in the pathophysiology of epilepsy can reduce the global disease burden. Probiotics are live, non-pathogenic microorganisms that benefit the host by regulating the gut microbiome. This review aims to study the effect of probiotics and ketogenic diets on gut microbiota and their potential as a therapy for epilepsy. We conducted a systematic search of the databases PubMed, Scopus, Embase, and the Web of Science for pertinent studies that have been published. Our search methodology was meticulously structured to be exhaustive, integrating targeted keywords and Boolean operators to guarantee the acquisition of all potentially pertinent articles. Probiotics interact with the gut microbiome, balance its composition, and influence the gut-brain axis. Moreover, they reduce neuroinflammation and oxidative stress. The ketogenic diet (KD) affects gut bacteria, influencing neurotransmitter levels and short-chain fatty acids (SCFAs), which play a role in the gut-brain axis. Studies have shown the positive effects of various probiotics in animal models of epilepsy. They demonstrate improvements in seizure activity, anxiety, and neuroinflammation. In human studies, probiotics reduced seizure frequency and enhanced quality of life in patients with drug-resistant epilepsy. We believe using probiotics or dietary interventions like KD could be a promising therapeutic strategy for managing epilepsy. This could reduce seizure frequency and make life better for patients with epilepsy.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":"14519-14543"},"PeriodicalIF":4.3,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144036635","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 Crosstalk Between Sepsis-Associated Encephalopathy and Alzheimer's Disease: Identifying Potential Biomarkers and Therapeutic Targets for Cognition.","authors":"Zhitong Wang, Zhiling Zhang, Jing Shi, Rongsheng Zhao","doi":"10.1007/s12035-025-05192-x","DOIUrl":"10.1007/s12035-025-05192-x","url":null,"abstract":"<p><p>Patients with sepsis are at a heightened risk of long-term cognitive impairment, including neurodegenerative diseases; however, the underlying pathophysiological mechanisms remain incompletely understood. This study examines key genes associated with sepsis and Alzheimer's disease (AD), as well as their potential molecular mechanisms. We downloaded the GSE135838 dataset from the Gene Expression Omnibus (GEO) database and performed comparative analysis of differentially expressed genes (DEGs) using the AlzData database to identify co-expressed DEGs. Functional and protein-protein interaction (PPI) network analyses were used to identify hub genes and their associated molecular mechanisms. Animal experiments were conducted to validate the role of the central gene C5aR1 in the pathological processes of sepsis-related cognitive impairment, blood-brain barrier (BBB) disruption, and microglial activation. Co-culture experiments were performed to assess the protective effect of C5aR1 against inflammation-induced neuronal damage. In GSE135838, 25 DEGs exhibited consistent expression changes in the brain tissue of AD patients. Notably, LYZ, C5AR1, ZFP36, MPZL2, APOL4, CD163, SERPINA3, and CCL2 showed significant differential expression in the cortex and hippocampus of AD patients. KEGG pathway enrichment analysis revealed that among the 14 pathways meeting the criteria, the TNF signaling pathway demonstrated the highest significance. Key intersections of multiple GO enrichment terms included IL-6, ICAM1, CLEC4E, and PCK1. The top ten hub genes identified from the PPI network analysis included IL6, CCL2, ICAM1, CXCL1, CD163, C5AR1, SOCS3, CLEC4E, HSPB1, and HSPA1A. Pharmacological inhibition of the hub gene product C5aR1 using PMX205 improved cognitive and emotional dysfunction in CLP-induced septic mice and reduced BBB damage and microglial activation. Inhibition of C5aR1 also alleviated microglia-induced neuronal injury. In summary, the neuroimmune dysregulation caused by sepsis is correlated with potential pathological mechanisms in AD. This study provides additional molecular evidence for potential biomarkers and therapeutic targets for drug intervention in the risk of AD among sepsis survivors.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":"13999-14014"},"PeriodicalIF":4.3,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144601016","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}