Molecular and Cellular Neuroscience最新文献

{"title":"A potential role for NADPH oxidase (NOX1/2) in mutant huntingtin-induced anomalous neurite outgrowth.","authors":"Luisana Duque Villegas, Alberte Vad Mathiesen, Izabela Rasmussen, Maria von Broich, Fillippa Liliendahl Qvist, Niels Skotte, Costanza Ferrari Bardile, Esben Budtz-Jørgensen, Kristine Freude, Benjamin Schmid, Mahmoud A Pouladi, Anne Nørremølle, Frederik Vilhardt","doi":"10.1016/j.mcn.2025.104012","DOIUrl":"https://doi.org/10.1016/j.mcn.2025.104012","url":null,"abstract":"<p><p>Neurite growth is regulated by NADPH Oxidase (NOX1 and 2) and in this study, we investigate whether neuritic abnormalities observed in stem cell models of Huntington's disease relates to altered NOX function during NGF-driven differentiation of PC12 neuronal cells. NOX1 and 2 were contained in separate vesicular compartments, and by overexpression inhibited or promoted neurite extension, respectively. Expression of mutant Htt (mHtt; exon 1 fragment) accelerated neuronal induction causing longer neurites in the first phase of differentiation, but fewer and shorter mature neurites. Htt/mHtt increased NOX2 protein levels but did not change global oxidant production; However, Htt/mHtt prominently redistributed NOX activity to neurites. Oxidant production was concentrated in intraluminal vesicles in multivesicular bodies, and mHtt specifically increased secretion of NOX1 in exosomes, which demonstrated oxidant production capacity, while rerouting NOX2 to lysosomal degradation. Knockdown of TSG101, required for intraluminal vesicle formation, increased cellular levels of NOX2/p22phox and neurite growth. Our study provides new insights on the disposition of NOX enzymes in nerve cells, indicating that deficient neurites in HD may be a correlate of altered trafficking, distribution, and activity of NOX.</p>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":" ","pages":"104012"},"PeriodicalIF":2.6,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144142961","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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 alarmins in neuroinflammation following spinal cord injury: A systematic review of the literature","authors":"Christian Rajkovic ,&nbsp;Donald MacElroy ,&nbsp;Eris Spirollari ,&nbsp;Sima Vazquez ,&nbsp;Galadu Subah ,&nbsp;Julianna Lazzari ,&nbsp;Sabrina L. Zeller ,&nbsp;John V. Wainwright ,&nbsp;Meena Jhanwar-Uniyal ,&nbsp;Merritt D. Kinon","doi":"10.1016/j.mcn.2025.104011","DOIUrl":"10.1016/j.mcn.2025.104011","url":null,"abstract":"<div><h3>Background</h3><div>Alarmins, or damage-associated molecular patterns (DAMPs), are a diverse class of molecules essential for cellular homeostasis; however, their activation following traumatic cell necrosis contributes to neuroinflammation leading to neurologic deficits. This review aims to highlight the current preclinical alarmin studies and define their neuroprotective role in the treatment of SCI.</div></div><div><h3>Methods</h3><div>A systematic review was performed to evaluate studies investigating alarmin-mediated immune and neuroinflammatory responses following SCI in animal models. Primary outcomes investigated included immunostaining of cell lines, quantification of alarmin, cytokine, and inflammatory mediators, myelin staining, and animal function scores.</div></div><div><h3>Results</h3><div>IL-1α, HMGB1, S100A1, MIF, D-DT, IL-33, heme, cell-free DNA, and extracellular nucleotides were found to act as alarmins in animal models of SCI. The expression of these molecules in neurons and neuroglia at the SCI lesion site increased levels of TNF-α, IL-1β, and iNOS, contributing to neuroinflammation. Induction of the neurotoxic phenotypes of macrophages, microglia, and astrocytes by IL-1α, HMGB1, and IL-33 promoted cell death and reduction in oligodendrocyte number. Inhibitors of alarmin-signaling pathways, such as toll-like receptors (TLRs), IL-1R1, RAGE, ST2, and mTOR improved neurological function, as shown by enhanced postoperative locomotion.</div></div><div><h3>Conclusions</h3><div>Elevated alarmin expression and activity at the SCI site contribute to functional deficits by augmenting neuroinflammation, cell death, and cytotoxic neuroglia. Targeting alarmin-mediated signaling pathways represents a promising therapeutic approach in SCI treatment.</div></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"133 ","pages":"Article 104011"},"PeriodicalIF":2.6,"publicationDate":"2025-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144099757","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Striatal damage may underlie motor learning impairment following experimental mild traumatic brain injury in mice","authors":"Caroline Amaral Machado ,&nbsp;Bruna da Silva Oliveira ,&nbsp;Heliana de Barros Fernandes ,&nbsp;Ricardo Tadeu de Carvalho ,&nbsp;Emanuele Tadeu Pozzolin ,&nbsp;Lucas Miranda Kangussu ,&nbsp;Brener Cunha Carvalho ,&nbsp;Antônio Lúcio Teixeira ,&nbsp;Aline Silva de Miranda","doi":"10.1016/j.mcn.2025.104013","DOIUrl":"10.1016/j.mcn.2025.104013","url":null,"abstract":"<div><div>The Renin-Angiotensin system (RAS) has receptors in key brain areas, including the striatum, and has been implicated in traumatic brain injury (TBI) outcomes through involvement in inflammation and oxidative stress. To date, whether striatal RAS dysregulation alongside inflammatory response and oxidative stress underlie mild TBI-related motor coordination and learning impairments remain to be explored. Herein, we employed a weight drop model to induce mild TBI (mTBI) in mice and investigate striatal damage at 72 h after the trauma. mTBI mice displayed significant decrease in the motor learning index and increase in the latency to fall in the rotarod compared with sham controls. In parallel, mTBI-mice had increased expression of RAS classical arm components AT1 and AT2 receptors along with a decrease in RAS counter-regulatory component Mas receptor in the ipsilateral striatum. The neurotrophic factor GDNF increased and the chemokine CX3CL1 decreased in the ipsilateral striatum while TNF-α enhanced in the contralateral striatum at 72 h after mTBI. Higher lipid peroxidation (TBARS) levels were found in both ipsilateral and contralateral striatum of mTBI mice compared with sham mice. We provided original evidence that changes in RAS, inflammatory, neurotrophic and oxidative stress responses in the striatum may contribute to motor dysfunction following acute mTBI.</div></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"133 ","pages":"Article 104013"},"PeriodicalIF":2.6,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144068630","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RNA-based therapies for neurodegenerative disease: Targeting molecular mechanisms for disease modification","authors":"Vishal Bhati,&nbsp;Sonima Prasad,&nbsp;Atul Kabra","doi":"10.1016/j.mcn.2025.104010","DOIUrl":"10.1016/j.mcn.2025.104010","url":null,"abstract":"<div><div>Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD) are characterized by progressive neuronal damage, protein aggregation, and chronic inflammation, leading to cognitive and motor impairments. Despite symptomatic relief from current therapies, disease-modifying treatments targeting the core molecular mechanism are still lacking. RNA-based therapies offer a promising approach to treating neurodegenerative disease by targeting molecular mechanisms such as gene expression, protein synthesis, and neuroinflammation. Therapeutic strategies include Long non-coding RNA (lncRNA), Antisense oligonucleotides (ASOs), RNA interference (RNAi), small interfering RNA (siRNA) and short hairpin RNA (shRNA), messenger RNA (mRNA) therapies, and microRNA (miRNA)-based interventions. These therapies aim to decrease toxic protein accumulation, restore deficient proteins, and modulate inflammatory responses in conditions like AD, PD, and HD. Unlike conventional treatments that primarily manage symptoms, RNA-based therapies have the potential to modify disease progression by addressing its root causes. This review aims to provide a comprehensive overview of current RNA-based therapeutic strategies for neurodegenerative diseases, discussing their mechanism of action, preclinical and clinical advancement. It further explores innovative solutions, including nanocarrier-mediated delivery, chemical modifications to enhance RNA stability, and personalized medicine approaches guided by genetic profiling that are being developed to overcome these barriers. This review also underscores the therapeutic opportunities and current limitations of RNA-based interventions, highlighting their potential to transform the future of neurodegenerative disease management.</div></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"133 ","pages":"Article 104010"},"PeriodicalIF":2.6,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143931379","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"One nanoparticle delivers two different neuroprotective amino acids into ischemic brain and protects against neuronal death in rat cerebral ischemia injury","authors":"Jingchen Gao,&nbsp;Xiyuran Wang,&nbsp;Qi Wan","doi":"10.1016/j.mcn.2025.104009","DOIUrl":"10.1016/j.mcn.2025.104009","url":null,"abstract":"<div><div>Previous studies have proven that glycine and proline are neuroprotective but have very low permeability through the blood-brain barrier (BBB), which is a major barrier to the application of these neuroprotective amino acids in the therapy of brain injury. In this study, we aimed to develop a therapeutic strategy by which one chitosan nanoparticle could deliver two different neuroprotective amino acids, glycine and proline, into the rat ischemic brain to confer neuroprotection in a rat model of cerebral ischemia-reperfusion (I/R) injury. Using the ion cross-linking method, we developed a preparation in which one chitosan nanoparticle was simultaneously loaded with glycine and proline (AA-NPs). We evaluated the therapeutic potential of AA-NPs in both cell and animal models of cerebral ischemic stroke. We found that the levels of glycine and proline were decreased in the brain tissues of I/R rats. AA-NPs delivered both glycine and proline into the ischemic brain and reduced ischemic neuronal death in both in vitro and in vivo. These results indicated that the dual delivery of glycine and proline via AA-NPs mediated neuroprotective effects, as evidenced by the reduction of neuronal death in both cellular and animal models of ischemic stroke. AA-NPs provide an efficient and potential delivery strategy by which multiple neuroprotective amino acids can be transported into the ischemic brain simultaneously for the treatment of ischemic stroke.</div></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"133 ","pages":"Article 104009"},"PeriodicalIF":2.6,"publicationDate":"2025-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143803828","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Estradiol activates the CaMKKβ/AMPK pathway to enhance neurite outgrowth in cultured adult sensory neurons","authors":"Pranav Mishra ,&nbsp;Benedict C. Albensi ,&nbsp;Paul Fernyhough","doi":"10.1016/j.mcn.2025.104008","DOIUrl":"10.1016/j.mcn.2025.104008","url":null,"abstract":"<div><div>Adult rat dorsal root ganglion (DRG) sensory neurons express estrogen receptors (ERs) α and β. Estrogen regulates multiple aspects of the nervous system including development, survival, and axonal outgrowth of DRG neurons. While previous studies have established estrogen's neuroprotective role in these neurons, the specific ER subtypes and downstream signaling pathways mediating these effects remain poorly defined. The objective of our study was to investigate the effects of 17 beta-estradiol (E2) on mitochondrial function and axonal regeneration of cultured DRG neurons and explore the pathways by which E2 acts. We observed that E2 treatment upregulated the levels of phosphorylated AMP-activated protein kinase (AMPK). E2 also increased the levels of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) and activating transcription factor 3 (ATF3), which are proteins involved in mitochondrial biogenesis and axonal regeneration. The Seahorse assay showed that E2 elevated basal respiration in cultured DRG neurons. Additionally, E2 treatment for 24 h significantly increased total neurite outgrowth of DRG neurons. Pharmacological inhibition of AMPK using Compound C inhibited E2-mediated increases in ATF3 expression and neurite outgrowth. The Ca²⁺/calmodulin-dependent protein kinase kinase β (CaMKKβ) inhibitor STO-609 blocked E2-mediated AMPK activation. Furthermore, we assessed whether these effects were mediated by ERα or ERβ by using the ERα selective agonist propyl pyrazole triol (PPT) and ERβ selective agonist diarylpropionitrile (DPN). PPT upregulated phosphorylated AMPK levels and increased total neurite outgrowth, whereas DPN was ineffective. The results demonstrate that E2 acts through ERα to promote neurite outgrowth <em>via</em> a pathway involving activation of CaMKKβ/AMPK in adult DRG neurons. Our findings identify ERα-mediated AMPK activation as a therapeutic target for enhancing neuronal regeneration and mitochondrial function in neurodegenerative disorders.</div></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"133 ","pages":"Article 104008"},"PeriodicalIF":2.6,"publicationDate":"2025-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143753579","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single subanesthetic dose of ketamine exerts antioxidant and antidepressive-like effect in ACTH-induced preclinical model of depression","authors":"Ana Ivanović ,&nbsp;Jelena Petrović ,&nbsp;Dušanka Stanić ,&nbsp;Jelena Nedeljković ,&nbsp;Miloš Ilić ,&nbsp;Marin M. Jukić ,&nbsp;Bojana Pejušković ,&nbsp;Vesna Pešić","doi":"10.1016/j.mcn.2025.104006","DOIUrl":"10.1016/j.mcn.2025.104006","url":null,"abstract":"<div><div>Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis and oxidative stress represent important mechanisms that have been implicated in etiopathology of depression. Although first antidepressants were introduced in clinical practice more than six decades ago, approximately 30 % of patients with a diagnosis of depression show treatment resistance. A noncompetitive <em>N</em>-methyl-<span>d</span>-aspartate receptor antagonist ketamine has shown promising rapid antidepressant effects and has been approved for treatment-resistant depression (TRD). In the present study, we investigated antioxidant and antidepressant-like activity of a single subanesthetic dose of ketamine (10 mg/kg, <em>ip</em>) in a rodent model of TRD induced by adrenocorticotropic hormone (10 μg ACTH/day, <em>sc</em>, 21 days). Behavioral assessment was performed, and plasma biomarkers of oxidative stress and DNA damage in peripheral blood lymphocytes (PBLs) were determined. We observed that ACTH produced depressive-like behavior and significant increase in superoxide anion (O₂^·-), advanced oxidation protein products (AOPP), malondialdehyde (MDA) and total oxidant status (TOS) in male Wistar rats. This effect was accompanied by reduced activity of antioxidant enzymes - superoxide dismutase (SOD) and paraoxonase1 (PON1) in plasma and increase in DNA damage in PBLs. In the described model of TRD, we have demonstrated antidepressant effects of ketamine for the first time. Our results reveal that ketamine was effective in reducing O₂^.-, AOPP, MDA and TOS, while enhancing SOD and PON1 activity in ACTH-rats. Collectively, our study sheds light on molecular mechanisms implicated in antioxidant activity of ketamine, thus incentivizing further investigation of its effects on ROS metabolism and antioxidant defenses in clinical trials, particularly in depression.</div></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"133 ","pages":"Article 104006"},"PeriodicalIF":2.6,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143743346","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Olfactory bulb interneurons – The developmental timeline and targeting defined by embryonic neurogenesis","authors":"Natalie J. Spence ,&nbsp;Eduardo Martin-Lopez ,&nbsp;Kimberly Han ,&nbsp;Marion Lefèvre ,&nbsp;Nathaniel W. Lange ,&nbsp;Bowen Brennan ,&nbsp;Charles A. Greer","doi":"10.1016/j.mcn.2025.104007","DOIUrl":"10.1016/j.mcn.2025.104007","url":null,"abstract":"<div><div>The generation of mouse olfactory bulb (OB) interneurons (INs) is initiated in the embryo but continues throughout life. It is generally agreed that OB INs generated postnatally affect the connectivity of the OB, depending on the timeline of neurogenesis. Here, we focused on OB INs generated embryonically, which have generally received less attention than those generated in the adult. Birthdates of embryonic INs were differentiated by maternal injections of thymidine analogs and their final destinations and phenotypes in the OB analyzed by immunohistochemistry. We found that the first embryonic INs were generated at embryonic day 10 (E10) and continued through the entire embryonic development. Analysis in adult tissues showed that embryonic INs were retained and were distributed across all layers of the OB. Interestingly, an initial lateral preference in cell density was seen in INs generated during E11–E13. Although INs are broadly distributed in the OB, we found that within the granule cell layer (GCL), OB INs distributed mostly in the superficial GCL. Immunostaining for calbindin, parvalbumin, tyrosine hydroxylase, 5T4 and calretinin were lacking co-expression with thymidine analogs labeled cells, suggesting that maturation of embryonic INs occurred slowly following birth. We studied the embryonic neuroblasts migration and differentiation by labeling IN progenitor cells in the lateral ganglionic eminence using in utero electroporation. We found that IN neuroblasts reached the primordial OB as early as E13 and began to differentiate apical dendrites by E15, which extended into the developing external plexiform layer. We established E16 as the embryonic stage at which the prototypical chain of migrating neuroblasts denoting the embryonic rostral migratory stream (RMS) was visible. Collectively, our data highlight the importance of studying OB INs in isolated time windows to better understand the formation of circuits that define the olfactory system function.</div></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"133 ","pages":"Article 104007"},"PeriodicalIF":2.6,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143692733","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exosome-based therapeutics: Advancing drug delivery for neurodegenerative diseases","authors":"Sakshi Rai ,&nbsp;Suman Kumar Ray ,&nbsp;Jagat R. Kanwar ,&nbsp;Sukhes Mukherjee","doi":"10.1016/j.mcn.2025.104004","DOIUrl":"10.1016/j.mcn.2025.104004","url":null,"abstract":"<div><div>Neurodegenerative disorders include Parkinson's disease, spinal cord injury, multiple sclerosis and Alzheimer's disease, cause gradual neuronal loss, protein misfolding, and accumulation, resulting in severe cognitive and movement deficits. Despite substantial study, therapeutic interventions are hampered by the blood-brain barrier, which prevents medication distribution to the central nervous system. Traditional pharmaceutical methods, such as small compounds, peptides, and inhibitors, have shown minimal effectiveness in addressing this obstacle. Exosomes are nanoscale membrane-bound vesicles that are primarily engaged in intercellular communication. They have the inherent capacity to cross the blood-brain barrier, which allows them to be used as medication delivery vehicles for brain illness therapy. Exosomes may be derived from a variety of cells like microglia, astrocytes identified according to origin, increasing their flexibility as drug delivery vehicles. Advanced engineering approaches optimise exosomes for tailored distribution across the blood-brain barrier, paving the path for novel neurodegenerative disease treatments. This review discusses the promise of exosome-based drug delivery, focussing on their composition, biogenesis, engineering, and applications in treating central nervous system illnesses, eventually overcoming the unmet hurdles of crossing the blood-brain barrier.</div></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"133 ","pages":"Article 104004"},"PeriodicalIF":2.6,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143692722","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GSK-3β dysregulation in aging: Implications for tau pathology and Alzheimer's disease progression","authors":"A. Rekha ,&nbsp;Muhammad Afzal ,&nbsp;M. Arockia Babu ,&nbsp;Soumya V. Menon ,&nbsp;Deepak Nathiya ,&nbsp;S. Supriya ,&nbsp;Shakti Bedanta Mishra ,&nbsp;Sofia Gupta ,&nbsp;Kavita Goyal ,&nbsp;Mohit Rana ,&nbsp;Haider Ali ,&nbsp;Mohd Imran","doi":"10.1016/j.mcn.2025.104005","DOIUrl":"10.1016/j.mcn.2025.104005","url":null,"abstract":"<div><div>The role of glycogen synthase kinase-3β (GSK-3β) in the pathogenesis of Alzheimer's disease (AD) is critical for linking amyloid-beta (Aβ) and Tau pathology. The activity of GSK-3β is dysregulated in the regulation of Tau hyperphosphorylation, formation of neurofibrillary tangles (NFTs), and production of Aβ by modulating amyloid precursor protein (APP) processing. This review discusses the mechanisms controlling GSK-3β dysregulation in aging and its influence on AD progression, focusing on the role of neuroinflammation, oxidative stress, and defective signaling pathways, including PI3K/Akt and Wnt. Critical analysis is presented for therapeutic strategies targeting GSK-3β using natural compounds (e.g., curcumin, geniposide) and emerging approaches such as TREM2 modulation and miRNA therapies. In preclinical models, these interventions promise to reduce Tau hyperphosphorylation and Aβ burden, along with associated neurodegeneration. Nevertheless, achieving selective GSK-3β inhibition and optimizing drug delivery are still critical barriers to clinical translation. This review underscores the central role of GSK-3β in AD pathogenesis to highlight its potential as a multifaceted therapeutic target of an innovative strategy for treating this complex neurodegenerative disease.</div></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"133 ","pages":"Article 104005"},"PeriodicalIF":2.6,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143692723","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}