{"title":"Roles for Exosomes from Various Cellular Sources in Spinal Cord Injury.","authors":"Wangnan Mao, Xinghao Liu, Chen Chen, Tongfu Luo, Zheng Yan, Lianguo Wu, Zhongcheng An","doi":"10.1007/s12035-025-05040-y","DOIUrl":"10.1007/s12035-025-05040-y","url":null,"abstract":"<p><p>Spinal cord injury (SCI) is a severe disorder characterized by regeneration challenges in the central nervous system (CNS), resulting in permanent paralysis, loss of sensation, and abnormal autonomic functions. The complex pathophysiology of SCI poses challenges to traditional treatments, highlighting the urgent need for novel treatment approaches. Exosomes have emerged as promising candidates for SCI therapy because of their ability to deliver a wide range of bioactive molecules, such as RNAs, proteins, and lipids, to target cells with minimal immunogenicity, which contribute to anti-inflammatory, anti-apoptotic, autophagic, angiogenic, neurogenic, and axon remodeling activities. In this study, we classified exosomes from different sources into four categories based on the characteristics of the donor cells (mesenchymal stem cells, neurogenic cells, immune cells, vascular-associated cells) and provided a detailed summary and discussion of the current research progress and future directions for each source. We also conducted an in-depth investigation into the applications of engineered exosomes in SCI therapy, focusing on their roles in drug delivery and combination with surface engineering technologies and tissue engineering strategies. Finally, the challenges and prospects of exosomal clinical applications in SCI repair are described.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":"14660-14682"},"PeriodicalIF":4.3,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144004588","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}
Molecular NeurobiologyPub Date : 2025-11-01Epub Date: 2025-05-13DOI: 10.1007/s12035-025-05039-5
Jonaid Ahmad Malik, Javed N Agrewala
{"title":"Assessing the Implications of Morphine-Induced Dysregulation of Autophagy on Brain Health.","authors":"Jonaid Ahmad Malik, Javed N Agrewala","doi":"10.1007/s12035-025-05039-5","DOIUrl":"10.1007/s12035-025-05039-5","url":null,"abstract":"<p><p>Morphine has been a widely used drug for pain management and anesthesia in clinical settings for centuries and is also a drug of abuse. Its illicit use by individuals with substance use disorders has resulted in numerous brain-related complications. The immunopharmacology of morphine is highly complex, necessitating a deeper understanding of its interactions with brain regions involved in learning and memory. Autophagy is a conserved physiological recycling process that degrades cytoplasmic organelles and proteins, repurposing their components for cellular function. However, recent studies indicate that morphine exposure disrupts autophagic processes, contributing to many morphine-associated complications. This article highlights recent advancements in understanding the interplay between morphine and autophagy. By exploring this intricate relationship, we aim to enhance our knowledge of morphine-associated complications and autophagy dysregulation, potentially improving the management of morphine use disorder and related conditions, thereby promoting healthier outcomes.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":"14706-14716"},"PeriodicalIF":4.3,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144032989","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}
Molecular NeurobiologyPub Date : 2025-11-01Epub Date: 2025-05-19DOI: 10.1007/s12035-025-05043-9
Náthaly Andrighetto Ruviaro, Patrícia Rodrigues, Julia Maria Frare, Gabriela Trevisan
{"title":"Ion Channels and G-Protein-Coupled Receptors Involved in the Development of Chronic Post-ischemic Pain (CPIP): A Model of Complex Regional Pain Syndrome (CRPS-I).","authors":"Náthaly Andrighetto Ruviaro, Patrícia Rodrigues, Julia Maria Frare, Gabriela Trevisan","doi":"10.1007/s12035-025-05043-9","DOIUrl":"10.1007/s12035-025-05043-9","url":null,"abstract":"<p><p>Chronic pain is a physical and emotional sensation that exceeds biological necessity. Complex regional pain syndrome (CRPS) is considered a chronic primary pain condition that can arise after limb trauma, such as surgery, ischemia, and fractures. This type of pain is a multifactorial disorder that predominantly affects one body extremity and occurs either without initial nerve injury (CRPS-I) or with partial or complete nerve injury (CRPS-II). Therefore, CRPS-I is still a painful and debilitating condition without a complete understanding of its underlying mechanisms. This gap in knowledge about CRPS-I pathophysiology contributes to patient suffering, as there is still no standard pharmacological treatment. Preclinical research uses diverse models of CRPS-I, such as chronic post-ischemia pain (CPIP), to better understand its pain activation pathways. Various mechanisms continue to emerge in CPIP, including the role of different G-protein-coupled receptors (GPCRs) and ion channels. In this review, we will focus on the mechanisms surrounding these different GPCRs and ion channels in a model of CRPS-I-induced nociception in rodents (the CPIP model). To date, the primary targets studied in CPIP pathophysiology include transient receptor potential (TRP) and N-methyl-D-aspartate (NMDA) ion channels, as well as cannabinoid, bradykinin, adenosine, adrenergic, and endothelin GPCRs.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":"14763-14776"},"PeriodicalIF":4.3,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144094168","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}
Molecular NeurobiologyPub Date : 2025-11-01Epub Date: 2025-06-04DOI: 10.1007/s12035-025-05115-w
Kun Wang, Xianfeng Qiu, Pan Fan, Lu Mao, Yangzhi Ren
{"title":"Knowledge Structure, Research Hotspots and Emerging Trends in the Role of miRNAs in Neuropathic Pain: a Quantitative Analysis Using Python.","authors":"Kun Wang, Xianfeng Qiu, Pan Fan, Lu Mao, Yangzhi Ren","doi":"10.1007/s12035-025-05115-w","DOIUrl":"10.1007/s12035-025-05115-w","url":null,"abstract":"<p><p>Neuropathic pain, caused by nerve injury or dysfunction, is a complex and chronic condition with limited treatment options beyond advances in pain management. MicroRNAs (miRNAs), which are small noncoding RNAs that regulate gene expression, play a critical role in pain modulation. The aim of this study was to identify research hotspots and trends in miRNA-related neuropathic pain studies, highlighting the potential of miRNAs as diagnostic biomarkers and therapeutic targets. A bibliometric analysis of 394 articles (2009-2024) retrieved from the Web of Science database was conducted, and Python was used to evaluate collaborations at the country, institutional, and individual levels, as well as keyword bursts, citation trends, and clustering. The analysis revealed a large increase in the number of publications, particularly from 2019 to 2022. China, the USA, and Germany are the leading contributors, with notable contributions from key researchers such as Zhang Yang and Su Zhen. Research is primarily focused on miRNAs in primary sensory neurons, apoptosis, bioinformatics, spinal cord injury, and biomarkers, but there are challenges that need to be addressed, including a narrow focus on specific miRNAs, isolated pathways, limited standardized evidence, and an overreliance on animal models. Future trends suggest expanding regulatory networks, analyzing interconnected pathways, standardizing protocols, and conducting clinical and human trials. This study provides researchers and clinicians a comprehensive overview of current research and future prospects in the field. Furthermore, this review can encourage clinicians to develop and improve miRNA-based therapies, offering new diagnostic and therapeutic strategies for neuropathic pain.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":"15093-15107"},"PeriodicalIF":4.3,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144216317","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 Intricate Relationship of Trk Receptors in Brain Diseases and Disorders.","authors":"Sarthak Dahiya, Poonam Sharma, Bhupesh Sharma, Priyanka Saroj, Harsha Kharkwal, Nitin Sharma","doi":"10.1007/s12035-025-05058-2","DOIUrl":"10.1007/s12035-025-05058-2","url":null,"abstract":"<p><p>The tropomyosin-related tyrosine kinases or neurotrophic tyrosine kinase receptors are a group of tyrosine kinases that play a crucial role in regulating neuronal growth and development. Neurotrophins are a class of protein-secreting cells that serve as the primary ligand for the Trk receptors. The four primary neurotrophins are nerve growth factor (NGF), brain-derived nerve factor (BDNF), neurotrophin-3, and neurotrophin-4/5. Mounting evidence suggests that Trk receptors can be categorized into three types: TrkA, TrkB, and TrkC. These receptors play a crucial role in facilitating neuronal growth and development. Trk receptors influence the survival and differentiation of neurons via many signalling cascades. Neurotrophin interaction with Trk receptors triggers a signalling cascade involving PLC, PI3K/Akt, and Ras/MAPK signalling pathways. Emerging evidence suggests that diminished neurotrophic support, changes in Trk receptor expression, or disruptions in signalling cascades play a crucial role in the development of various neurological disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), autism spectrum disorder (ASD), and many more. This review specifically explores therapeutic approaches targeting Trk receptors, their ligands, and Trk signaling in the context of various brain disorders. We focus on the potential for modulating or inhibiting Trk receptors as a treatment strategy for brain diseases.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":"14883-14922"},"PeriodicalIF":4.3,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144128016","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}
Molecular NeurobiologyPub Date : 2025-11-01Epub Date: 2025-07-01DOI: 10.1007/s12035-025-05176-x
Tamanna Khatun, Abdul Malik, Abdullah K Alshememry, Rubel Hasan, Md Shimul Bhuia, Raihan Chowdhury, Sabiha Fatima, Dipu Bishwas, Sonaly Akter Mukty, Ishrat Jahan Disha, Mehedi Hasan Bappi, Muhammad Torequl Islam
{"title":"Synergistic Sedative Activity of Indirubin on Diazepam in Thiopental Sodium-induced Sleeping Mice: A Potential GABAergic Transmission.","authors":"Tamanna Khatun, Abdul Malik, Abdullah K Alshememry, Rubel Hasan, Md Shimul Bhuia, Raihan Chowdhury, Sabiha Fatima, Dipu Bishwas, Sonaly Akter Mukty, Ishrat Jahan Disha, Mehedi Hasan Bappi, Muhammad Torequl Islam","doi":"10.1007/s12035-025-05176-x","DOIUrl":"10.1007/s12035-025-05176-x","url":null,"abstract":"<p><p>Insomnia remains one of the most common sleep disorders and causes significant discomfort as well as impairment in social, interpersonal, and vocational aspects of life. This study focuses on assessing the sedative activity of indigo naturalis indirubin (IND) on thiopental sodium (TS)-induced sleeping mice and evaluating the underlying molecular mechanisms through an in silico study. The adult male Swiss albino mice were used and given IND (5 and 10 mg/kg, i.p.), and diazepam (DZP) (2 mg/kg) in the respective groups individually and in combination to investigate modulatory effects. After 30 min, the treated mice were given TS (20 mg/kg, i.p.) to promote sleep, and the latency and duration of sleep were recorded manually. The in vivo study revealed that a higher dose of test sample (IND-10 mg/kg) showed lower latency and higher sleeping duration than a lower dose. Furthermore, an in silico study was performed to predict the involvement of gamma-aminobutyric acid (GABA) receptors in the sleep mechanism and assess pharmacokinetics and toxicity. Findings revealed that IND increased the duration of sleeping and decreased the latency of sleep induction. Additionally. the combination therapy of IND and DZP demonstrated synergistic sedative activity, as indicated by a greater reduction in locomotor activity and increased duration of sedation compared to either drug alone. IND exhibited a higher binding affinity (-9.1 kcal/mol) than DZP (-8.3 kcal/mol) at the identical binding site in the in silico study. The pharmacokinetic analysis of IND indicated acceptable drug-likeness and good pharmacokinetic properties. In conclusion, IND produced a potent sedative effect in the mouse model, possibly through the GABA<sub>A</sub> receptor interaction pathways.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":"13827-13839"},"PeriodicalIF":4.3,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144540961","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}
Molecular NeurobiologyPub Date : 2025-11-01Epub Date: 2025-06-04DOI: 10.1007/s12035-025-05098-8
Hayder M Al-Kuraishy, Ghassan M Sulaiman, Hebatallah M Saad, Hamdoon A Mohammed, Mosleh M Abomughaid, Ali I Al-Gareeb, Ali K Albuhadily
{"title":"The Effect of Metformin on Astrocytes in Parkinson's Disease: Challenges and Opportunities.","authors":"Hayder M Al-Kuraishy, Ghassan M Sulaiman, Hebatallah M Saad, Hamdoon A Mohammed, Mosleh M Abomughaid, Ali I Al-Gareeb, Ali K Albuhadily","doi":"10.1007/s12035-025-05098-8","DOIUrl":"10.1007/s12035-025-05098-8","url":null,"abstract":"<p><p>Parkinson's disease (PD) is a progressive neurodegenerative disease that represents the most common movement disorder in old-age subjects. The development of PD neuropathology is due to the progressive accumulation of alpha-synuclein (α-Syn) in the dopaminergic neurons of the substantia nigra pars compacta (SNpc). Moreover, astrocytes are intricate in the pathogenesis of PD that has neuroprotective effects against oxidative stress in PD by releasing antioxidant and anti-inflammatory mediators. The physiological properties of astrocytes are altered in PD due to the progressive accumulation of α-Syn, which induces mitochondrial dysfunction, oxidative stress, and inflammation. In addition, genetic mutations in PD also impact the antioxidant and anti-inflammatory properties of astrocytes. The functional role of astrocytes is extremely distorted in PD. Therefore, restoration of the anti-inflammatory and antioxidant effects of astrocytes could be an alternative therapeutic strategy in the management of PD. It has been shown that the anti-diabetic metformin improves the anti-inflammatory and antioxidant effects of astrocytes in different neurodegenerative diseases, including PD. Nevertheless, the mechanisms that relate to the effect of metformin on astrocytes in PD are not completely elucidated. Consequently, this review aims to discuss the astroprotective effect of metformin in PD with regard to the underlying mechanisms.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":"15055-15069"},"PeriodicalIF":4.3,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144216374","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}
Molecular NeurobiologyPub Date : 2025-11-01Epub Date: 2025-07-02DOI: 10.1007/s12035-025-05182-z
Sara Taremi Horoufi, Davood Zaeifi
{"title":"Pathway Analysis and Genetic Markers in Parkinson's Disease: Insights into Subtype-Specific Mechanisms.","authors":"Sara Taremi Horoufi, Davood Zaeifi","doi":"10.1007/s12035-025-05182-z","DOIUrl":"10.1007/s12035-025-05182-z","url":null,"abstract":"<p><p>Parkinson's disease (PD) is a complex disease influenced by both genetic and environmental factors. Despite advances in understanding PD genetics, subtype-specific mechanisms remain poorly characterized. This study aims to identify distinct genetic markers and pathways across PD subtypes, addressing this gap to enable targeted diagnostics and therapies. Genes associated with PD were collected from various databases and categorized into groups based on the PD type to assess the PD risk. Protein interaction analysis was conducted to identify functional clusters and key genes within each group. KEGG enrichment analysis revealed common genes and pathways among the different PD groups. This study conformed to the PRISMA 2020 guidelines for systematic data collection and analysis. Hub genes such as PRKN, SNCA, and LRRK2 have demonstrated considerable potential as biomarkers for genetic predisposition in PD, alongside the identification of additional complementary genes. Analysis of hub node variants highlighted specific genetic variations in these genes. We identified several microRNAs, including hsa-miR-335-5p, hsa-miR-19a-3p, and hsa-miR-106a-5p, as well as transcription factors that interact with crucial hub genes. This study refines subtype-specific mechanisms for established PD genes and identifies novel genetic markers and pathways associated with juvenile, young-onset, late-onset, familial, and sporadic Parkinson's disease, enhancing our understanding of their molecular mechanisms and potential for targeted diagnostics and therapies. Specifically, we highlight the roles of hub genes, such as PRKN, SNCA, and LRRK2, alongside significant microRNA interactions, which may serve as biomarkers for early detection and personalized treatment approaches.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":"13858-13877"},"PeriodicalIF":4.3,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144540960","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}
Molecular NeurobiologyPub Date : 2025-11-01Epub Date: 2025-06-13DOI: 10.1007/s12035-025-05121-y
Junbiao Tu
{"title":"Polyphenols and Exercise in Mitochondrial Biogenesis: Focus on Age-Related CNS Disorders.","authors":"Junbiao Tu","doi":"10.1007/s12035-025-05121-y","DOIUrl":"10.1007/s12035-025-05121-y","url":null,"abstract":"<p><p>Age-related central nervous system (CNS) disorders, including neurodegenerative diseases, represent a growing global health burden. Mitochondrial dysfunction is a recognized hallmark in the pathogenesis of these conditions, emphasizing the critical importance of maintaining neuronal energy homeostasis and cellular integrity. Mitochondrial biogenesis, the dynamic process of generating new, functional mitochondria, is paramount for neuronal health and resilience against age-related decline. This review investigates the therapeutic potential of physical activity and polyphenols in modulating mitochondrial biogenesis and offering neuroprotection within the context of age-related CNS disorders. We explore how regular exercise profoundly impacts the brain by enhancing synaptic plasticity, promoting neurogenesis via neurotrophic factors like BDNF, and stimulating mitochondrial biogenesis through pathways such as PGC-1alpha activation. These adaptations collectively improve cognitive function and bolster neuronal resistance to damage. Concurrently, polyphenols, known for their antioxidant and anti-inflammatory properties, demonstrate significant neuroprotective effects. They are capable of crossing the blood-brain barrier and influencing key neuronal signaling pathways, directly stimulating mitochondrial biogenesis, and mitigating oxidative stress, thereby supporting neuronal survival. By synthesizing current evidence, this review highlights the complementary and potentially synergistic roles of exercise and polyphenols in preserving mitochondrial health and function in the CNS. The combined impact of these interventions offers a promising non-pharmacological strategy to combat age-related neurodegeneration. Future research should focus on optimizing exercise protocols and polyphenol interventions in human trials to maximize their neurotherapeutic benefits for CNS disorders.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":"15164-15188"},"PeriodicalIF":4.3,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144285508","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}
Molecular NeurobiologyPub Date : 2025-11-01Epub Date: 2025-05-22DOI: 10.1007/s12035-025-05051-9
Sama Ayoub, Maryam Arabi, Yousef Al-Najjar, Ibrahim Laswi, Tiago F Outeiro, Ali Chaari
{"title":"Glycation in Alzheimer's Disease and Type 2 Diabetes: The Prospect of Dual Drug Approaches for Therapeutic Interventions.","authors":"Sama Ayoub, Maryam Arabi, Yousef Al-Najjar, Ibrahim Laswi, Tiago F Outeiro, Ali Chaari","doi":"10.1007/s12035-025-05051-9","DOIUrl":"10.1007/s12035-025-05051-9","url":null,"abstract":"<p><p>As global life expectancy increases, the prevalence of neurodegenerative diseases like Alzheimer's disease (AD) continues to rise. Since therapeutic options are minimal, a deeper understanding of the pathophysiology is essential for improved diagnosis and treatments. AD is marked by the aggregation of Aβ proteins, tau hyperphosphorylation, and progressive neuronal loss, though its precise origins remain poorly understood. Meanwhile, type 2 diabetes mellitus (T2DM) is characterized by chronic hyperglycemia, leading to the formation of advanced glycation end products (AGEs), which are implicated in tissue damage and neurotoxicity. These AGEs can be resistant to proteolysis and, therefore, accumulate, exacerbating AD pathology and accelerating neurodegeneration. Insulin resistance, a hallmark of T2DM, further complicates AD pathogenesis by promoting tau hyperphosphorylation and Aβ plaque accumulation. Additionally, gut microbiome dysbiosis in T2DM fosters AGE accumulation and neuroinflammation, underscoring the intricate relationship between metabolic disorders, gut health, and neurodegenerative processes. This complex interplay presents both a challenge and a potential avenue for therapeutic intervention. Emerging evidence suggests that antidiabetic medications may offer cognitive benefits in AD, as well as in other neurodegenerative conditions, pointing to a shared pathophysiology. Thus, we posit that targeting AGEs, insulin signaling, and gut microbiota dynamics presents promising opportunities for innovative treatment approaches in AD and T2DM.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":"14859-14882"},"PeriodicalIF":4.3,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12511161/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144119511","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}