Molecular Neurobiology最新文献

{"title":"Verification of Pain-Related Neuromodulation Mechanisms of Calcitonin in Knee Osteoarthritis.","authors":"Qing Lin, Xue Tan, Dezun Ma, Yanfeng Huang, Lili Wang, Danhao Zheng, Jiaqiu Lin, Zaishi Zhu, Min Mao, Zhouping Yi, Jie Wang, Xihai Li","doi":"10.1007/s12035-025-04707-w","DOIUrl":"10.1007/s12035-025-04707-w","url":null,"abstract":"<p><p>Chronic pain represents the prevailing symptom among patients suffering from knee osteoarthritis (KOA). In KOA, peripheral sensitization is driven by disruptions in subchondral bone homeostasis, local inflammatory responses, and variations in neuropeptide and neurotransmitter levels. Calcitonin, a pivotal peptide involved in bone metabolism, additionally exhibits potent analgesic properties. This study aimed to elucidate the mechanisms underlying calcitonin's neuromodulatory effects related to pain in the treatment of KOA. Three experiments were conducted: (1) assessing calcitonin's therapeutic effects via histomorphology, nociceptive behavioral assessments, and Western blot analysis of proteins; (2) verification of the involvement of neurotransmitters and neuropeptides in calcitonin's action using the Signal Transduction PathwayFinder PCR Array, Bio-Plex suspension chip, and ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS); and (3) exploration of calcitonin's impact on brain function through functional magnetic resonance imaging (fMRI). Experiment 1 validated calcitonin's efficacy in KOA models. Experiment 2 demonstrated the involvement of the retinoic acid signaling pathway in calcitonin treatment, confirming that its analgesic efficacy is associated with the modulation of neuropeptides and neurotransmitters. Experiment 3 revealed that calcitonin treatment could reverse regional homogeneity and amplitude of low-frequency fluctuations in the hippocampus and tegmental nucleus. The study affirmed the critical role of pain-related neuromodulation mechanisms in calcitonin treatment, demonstrating that its analgesic effects are mediated through the modulation of neurotransmitters, neuropeptides, and brain function, as observed via fMRI. These findings provide a theoretical foundation for the clinical application of calcitonin in the treatment of KOA pain.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":"8341-8358"},"PeriodicalIF":4.6,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143492931","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 Guanylate Cyclase Soluble Subunit Alpha-1 Deficiency Impairs Angiogenesis in Zebrafishes and Mice: In Vivo and In Vitro Studies.","authors":"Man Luo, Dongcan Mo, Jianli Li, LiuYu Liu, Xiaoling Li, Jing Lin, Jie Liang, Fei Ye, Xiaozuo Lin, Pingkai Wang, Xiaoju Wu, Yinan Zeng, Jiaoxing Li, Wenli Sheng","doi":"10.1007/s12035-025-04763-2","DOIUrl":"10.1007/s12035-025-04763-2","url":null,"abstract":"<p><p>Moyamoya disease (MMD) is caused by abnormal vascular development. Guanylate cyclase soluble subunit alpha-1 (GUCY1A3) gene variation is verified as a crucial susceptible gene in MMD. In this study, we investigated the impact of GUCY1A3 on angiogenesis. GUCY1A3-knockout (KO) models were established using CRISPR/Cas9 technology in zebrafishes and mice. Blood vessel distribution in GUCY1A3-KO zebrafishes and retinal angiogenesis in postnatal GUCY1A3-KO mice were analyzed. Anti-angiogenic behaviors, including cell proliferation, migration, and apoptosis, and changes in hypoxia-inducible factor-1α (HIF-1α) distribution were examined in GUCY1A3-knockdown (KD) mice brain microvascular endothelial cells (BMECs). GUCY1A3-KO significantly decreased intracranial central artery development in zebrafishes, delayed retinal vascularization in mice, reduced retinal vascular endothelial growth factor A (VEGFA) expression in mice, and abolished expression of the GUCY1A3-encoded protein, α1 subunit of soluble guanylate cyclase. GUCY1A3-KD significantly decreased cell proliferation (flow cytometry analysis) and migration (wound-healing and Transwell assays), but increased apoptosis (hypoxia-induced apoptosis assay) in the BMECs. Immunofluorescence of HIF-1α revealed that nuclear translocation and protein expression were significantly reduced in the GUCY1A3-KD BMECs. These findings indicated that decreased expression of GUCY1A3 resulted in anti-angiogenic activity through inhibiting VEGFA and HIF-1α expression and nuclear translocation, inhibiting endothelial cell proliferation and migration, and promoting endothelial cell apoptosis.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":"8248-8260"},"PeriodicalIF":4.6,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143492920","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":"Silencing YTHDF2 Induces Apoptosis of Neuroblastoma Cells In a Cell Line-Dependent Manner via Regulating the Expression of DLK1.","authors":"Zhongyan Hua, Baocheng Gong, Zhijie Li","doi":"10.1007/s12035-025-04759-y","DOIUrl":"10.1007/s12035-025-04759-y","url":null,"abstract":"<p><p>Neuroblastoma (NB) is the most common extracranial malignant solid tumor in children. The complications caused by traditional chemoradiotherapy seriously affect the quality of life of patients with NB. In this study, NGP, KCNR, and SH-SY5Y (SY5Y) cell lines were used. Retinoic acid (RA, 5 µM) was used to treat NB cells for 48 h. siRNAs were used to silence the expression of DLK1 or YTHDF2. Cell confluence was analyzed using IncuCyte ZOOM to evaluate cell proliferation of NB cells. RT-qPCR and western blotting were performed to detect the expression of target molecules. Annexin V/PI staining and Caspase-Glo 3/7 assay were performed to detect cell apoptosis. RNA m6A quantification, MeRIP-qPCR, and RIP-qPCR were performed. Results showed that RA treatment decreased the expression of DLK1 and YTHDF2 in NB cells, and low expression of DLK1 was correlated with good prognosis of patients. Knockdown of the expression of DLK1 or YTHDF2 inhibited cell proliferation and induced apoptosis of SY5Y cells, but not NGP and KCNR cells. Furthermore, we found that there are m6A modification sites in DLK1 mRNA, and the expression of m6A modified DLK1 mRNA increased after RA treatment, and YTHDF2 regulates the expression level of DLK1, and the expression of YTHDF2-bound DLK1 mRNA decreased after RA treatment. These suggest that YTHDF2 may regulate the proliferation and apoptosis of NB cells in a cell line-dependent manner by binding to the m6A modification site of DLK1 mRNA to affect its expression, and YTHDF2 and DLK1 are potential therapeutic targets for patients with NB.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":"8121-8134"},"PeriodicalIF":4.6,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143468739","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":"Long-lasting Depressive Behavior of Adolescent Chronically Stressed Mice is Mediated by Gut Microbiota Dysbiosis.","authors":"Iva Lukic, Sanja Ivkovic, Emilija Glavonic, Miroslav Adzic, Milos Mitic","doi":"10.1007/s12035-025-04757-0","DOIUrl":"10.1007/s12035-025-04757-0","url":null,"abstract":"<p><p>Depression is one of the most common mental disorders worldwide, and its prevalence sharply rises during adolescence. Adolescence is a particularly sensitive period to the effects of environmental stressors, which can cause persistent depressive behavior extending into adulthood. However, the studies assessing if changes in gut microbiota could be one of the mediators of long-term effects of adolescent stress are scarce. In the present study, we examined enduring effects of adolescent chronic unpredictable stress (CUS) on mice behavior along with alterations in their gut microbiome, by using 16 s rRNA gene sequencing and fecal microbiota transplantation (FMT). CUS mice, as well as naïve mice receiving FMT from stressed animals, showed long-lasting anxiety and depressive-like behavior extending into adulthood. The microbiota dysbiosis in adolescence was characterized by higher abundance of Alloprevotella and lower abundance of Paraprevotella, Parasutterella, Parabacteroides, and undefined genus Rikenellaceae_RC9_gut_group. On the contrary, microbiota dysbiosis in adulthood was characterized by higher abundance of Bacteroides, Enterorhabdus, Marvinbriantia, and Parabacteroides and lower abundance of Akkermansia, Odoribacter, and Rikenella. In particular, depressive-like behavior in adolescence was negatively correlated with Paraprevotella, while depressive-like behavior in adulthood was negatively correlated with Rikenella abundance, in both CUS and FMT mice. Therefore, the transfer of microbiota from mice stressed in adolescence is able to induce long-lasting depressive-like behavior in naïve mice, clearly showing the importance of gut microbiota dysbiosis in adolescence in shaping enduring depressive behavior. Moreover, our results indicate that changes in specific but different bacteria are related to depressive behavior in adolescence and in adulthood.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":"8868-8886"},"PeriodicalIF":4.6,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143573380","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":"ROS Regulate Rotenone-induced SH-SY5Y Dopamine Neuron Death Through Ferroptosis-mediated Autophagy and Apoptosis.","authors":"Xinying Li, Weiran Li, Xinying Xie, Ting Fang, Jingwen Yang, Yue Shen, Yicheng Wang, Hongyan Wang, Liqing Tao, Heng Zhang","doi":"10.1007/s12035-025-04824-6","DOIUrl":"10.1007/s12035-025-04824-6","url":null,"abstract":"<p><p>Rotenone, a plant-derived natural insecticide, is widely used to induce Parkinson's disease (PD) models. However, the mechanisms of rotenone-induced cell death remain unclear. Here, we found that rotenone (0.01, 0.1, or 1 μmol/L) suppressed SH-SY5Y dopamine neuron viability and led to PD-like pathological changes, such as reduced tyrosine hydroxylase (TH) but increased α-synuclein. Rotenone increased the levels of intracellular reactive oxygen species (ROS) and mitochondrial ROS, as well as the levels of the antioxidants nuclear factor E2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1), ultimately resulting in oxidative stress. Moreover, rotenone significantly downregulated the expression of GPX4 and xCT but upregulated the expression of COX2 and NCOA4, which are markers of ferroptosis. Furthermore, rotenone decreased phosphorylated mTOR level but increased Beclin-1, ATG5, LC3 and p62 expression, suggesting that rotenone enhances autophagy and reduces autophagy flux. Additionally, rotenone reduced Bcl-2 levels and the mitochondrial membrane potential (MMP) while promoting BAX and Caspase-3 expression, thus initiating cell apoptosis. N-acetylcysteine (NAC), a ROS scavenger, and ferrostatin-1 (Fer-1) and deferoxamine (DFO), two ferroptosis inhibitors, significantly eliminated rotenone-induced autophagy and apoptosis. Moreover, ML385, a specific inhibitor of Nrf2, suppressed rotenone-induced ferroptosis. Our results demonstrated that ROS might mediate rotenone-induced PD-like pathological changes by regulating iron death, autophagy, and apoptosis. Inhibiting ferroptosis blocked the rotenone-induced increase in autophagy and apoptosis. Thus, the ability of ROS to regulate rotenone-induced death through autophagy and apoptosis is dependent on ferroptosis. The findings require validation in multiple neuronal cell lines and in vivo.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":"9271-9289"},"PeriodicalIF":4.6,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143649555","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":"Nano-mediated Management of Metal Toxicity-induced Neurodegeneration: A Critical Review.","authors":"Priyanshu Rajesh Dubey, Gagandeep Kaur, Rahul Shukla","doi":"10.1007/s12035-025-04782-z","DOIUrl":"10.1007/s12035-025-04782-z","url":null,"abstract":"<p><p>Heavy metals, omnipresent in the environment, though imperative in trace quantities for human physiology, become a serious health hazard due to their toxicity. Copper, arsenic, lead, iron, and mercury are some examples of the heavy metals responsible for oxidative stress, which is one of the primary factors behind neurodegenerative diseases like Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis. Neurodegeneration is caused by toxicity due to environmental exposure to these toxic substances or genetic variation. Conventional therapies, relying on chelation and antioxidants, suffer from the broader perspective of metal removal in a non-selective manner and poor targeting of the brain. In this respect, treatments based on nanotechnology that employ nanoparticles such as dendrimers, micelles, and liposomes constitute a promising interest in enhancing drug delivery with minimal neurotoxicity. The present review outlines the heavy metals responsible for neurodegenerative diseases, their pathophysiology, management strategies available at present, and the scope of nanotechnology intervention in overcoming shortcomings of conventional therapies. The genetic influence of heavy metals on neurological health is also part of this article.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":"8400-8419"},"PeriodicalIF":4.6,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143492919","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":"Emodin, a Potent Anthraquinone Mitigates MPTP-Induced Parkinsons' Disease Pathology by Regulating Nrf2 and Its Downstream Targets: In Silico and In Vivo Approach.","authors":"Sarwat Jahan, Muhammad Ikram, Sami Siraj, Shakir Ullah, Muhammad Zakria, Nasir Ahmad","doi":"10.1007/s12035-025-04762-3","DOIUrl":"10.1007/s12035-025-04762-3","url":null,"abstract":"<p><p>Parkinson's disease (PD) is marked by neurodegeneration that follows the destruction of dopaminergic neurons, mainly localized to the substantia nigra. It results in debilitating motor as well as non-motor symptoms. The current study investigated the neuroprotective potential of emodin, a naturally occurring anthraquinone derivative, in a well-established model of PD in mice induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The key focus is the Nrf2 signaling pathway, the major defense mechanism of the cells against oxidative damage and neuroinflammation, both exacerbated in the pathology of PD. Using molecular docking, the binding affinity of emodin to Nrf2 was predicted, revealing strong interactions that suggest emodin's potential to activate Nrf2. Subsequently, in vivo experiments were conducted where MPTP-induced PD mice were treated with emodin, and additional groups received Nrf2 modulators: dimethyl fumarate (DMF) as an agonist and all-trans retinoic acid (ATRA) as an antagonist. Emodin treatment led to a significant upregulation of Nrf2 expression, a reduction in oxidative stress markers such as malondialdehyde, and notable improvements in motor and cognitive behavior. DMF co-administration enhanced emodin's neuroprotective effects, whereas ATRA diminished them, highlighting the central role of Nrf2. These findings suggest that emodin effectively targets PD pathology via the Nrf2 pathway.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":"8103-8120"},"PeriodicalIF":4.6,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143458664","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 Nrf2 Signaling Pathway by Tetrahydroberberine Suppresses Ferroptosis and Enhances Functional Recovery Following Spinal Cord Injury.","authors":"Xiang Li, Heng Yu, Rongjie Liu, Jiansen Miao, Junlei Lv, Shu Yang, Yuxuan Zhu, Yan Chen, Keyu Lu, Chongan Huang, Xiangyang Wang","doi":"10.1007/s12035-025-04791-y","DOIUrl":"10.1007/s12035-025-04791-y","url":null,"abstract":"<p><p>Recent research has identified ferroptosis, a newly recognized form of programmed cell death, is a crucial factor in spinal cord injury (SCI). Tetrahydroberberine (THB) is a tetrahydroisoquinoline alkaloid derived from the tuber of the poppy family plant, Corydalis, which is recognized for its antioxidant and neuroprotective properties. Despite these attributes, the potential protective effects of THB against SCI are yet to be thoroughly investigated. Therefore, the aim of this study was to elucidate the protective effects and underlying mechanisms of action of THB in SCI. A mouse model of SCI was used for the in vivo experiments. Functional recovery was evaluated using the Basso Mouse Scale (BMS), footprint analysis, and hematoxylin and eosin (HE), Masson's trichrome, and Nissl staining. Lipid peroxidation was quantified using malondialdehyde (MDA), glutathione (GSH), and superoxide dismutase (SOD). The expression levels of the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway and ferroptosis markers were analyzed using western blot (WB) and immunofluorescence (IF) staining. To further elucidate the mechanism through which THB inhibits ferroptosis, an in vitro ferroptosis model was established in PC12 cells using RSL3, a known ferroptosis activator. THB markedly improved tissue and motor function restoration in mice post-SCI, with the BMS score increasing by approximately 50% compared with that in the control group. Lipid peroxidation assays revealed that THB significantly reduced MDA levels and increased GSH and SOD levels. Both in vivo and in vitro experiments demonstrated that THB significantly activated the Nrf2 pathway and inhibited ferroptosis in mice and in PC12 cells. This protective effect was reversed by the Nrf2 inhibitor, ML385, as evidenced by suppression of the Nrf2 pathway, increased lipid peroxidation, and elevated ferroptosis levels. Our in vivo and in vitro experiments indicate that THB promotes functional recovery after SCI by activating the Nrf2 signaling pathway, which attenuates lipid peroxidation and suppresses ferroptosis, thereby contributing to neuronal survival. Our findings contribute to a more comprehensive understanding of how THB exerts its recovery effects in SCI and demonstrate the potential of THB as a novel therapeutic strategy for the clinical management of SCI.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":"8439-8456"},"PeriodicalIF":4.6,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143516190","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 Role of MicroRNAs in Neurodegeneration: Insights from Huntington's Disease.","authors":"Reda M Mansour, Abanoub A S Shaker, Ahmed I Abulsoud, Sherif S Abdel Mageed, Alaa Ashraf, Elsayed G E Elsakka, Mohammed I Dahab, Mohamed M Sadek, Farah A Awad, Radwa H Lutfy, Hanan Elimam, Ahmed H I Faraag, Yara A Nassar, Mohamed A Ali, Osama A Mohammed, Mustafa Ahmed Abdel-Reheim, Ahmed S Doghish","doi":"10.1007/s12035-025-04750-7","DOIUrl":"10.1007/s12035-025-04750-7","url":null,"abstract":"<p><p>MicroRNA (miRNAs) is a single non-coding strand with a small sequence of approximately 21-25 nucleotides, which could be a biomarker or act as a therapeutic agent for disease. This review explores the dynamic role of miRNAs in Huntington's disease (HD), encompassing their regulatory function, potential as diagnostic biomarker tools, and emerging therapeutic applications. We delved into the dysregulation of specific miRNAs in HD, for instance, downregulated levels of miR-9 and miR-124 and increased levels of miR-155 and miR-196a. These alterations highlight the promise of miRNAs as non-invasive tools for early HD detection and disease progression monitoring. Moving beyond diagnosis, the exciting potential of miRNA-based therapies. By mimicking downregulated miRNAs or inhibiting dysregulated ones, we can potentially restore the balance of mutant target gene expression and modify disease progression. Recent research using engineered miRNAs delivered via an adeno-associated virus (AAV) vector in a transgenic HD minipig model demonstrates encouraging results in reducing mutant HD and improving motor function.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":"8502-8517"},"PeriodicalIF":4.6,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143502672","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":"Unlocking the Therapeutic Potential of the Dual-Specificity Tyrosine Phosphorylation-Regulated Kinase 1A Inhibitors in Alzheimer's Diseases.","authors":"Dipanjan Karati, Shreyasi Meur, Ankur Saha, Trina Saha, Aratrika Sen","doi":"10.1007/s12035-025-04806-8","DOIUrl":"10.1007/s12035-025-04806-8","url":null,"abstract":"<p><p>With 60-70% of all occurrences of dementia, Alzheimer's disease (AD), an advancing neurological illness, is one of the most frequent causes of dementia. Even though the exact etiology of AD is still unidentified, persons who have the disease have been found to have a number of abnormalities in their brains. Apart from the buildup of amyloid-β plaques inside the brain tissue, it has been demonstrated that abnormal tau protein phosphorylation increases the risk of neuronal death. The discovery of dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) is becoming increasingly significant in the fight to create efficacious Alzheimer's disease (AD) therapies. The pathophysiology of AD, which includes the creation of amyloid plaques and tau hyperphosphorylation, is intimately connected with the dysregulation of DYRK1A, which is essential for neurodevelopment and cognitive function. In addition to amyloid plaques, DYRK1A phosphorylates tau on 11 distinct Ser/Thr residues, forming aggregates known as \"neurofibrillary tangles\" that may be the cause of dementia, neuronal degeneration, and cell death. Therefore, targeting DYRK1A with small molecules may be a promising therapy strategy for Alzheimer's and other neurodegenerative illnesses. This study examines the therapeutic potential of DYRK1A inhibitors in AD and offers a thorough explanation of the molecular pathways through which DYRK1A promotes the development of the illness.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":"8809-8823"},"PeriodicalIF":4.6,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143567643","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}