NeuroMolecular Medicine最新文献

{"title":"Tau from SPAM Transgenic Mice Exhibit Potent Strain-Specific Prion-Like Seeding Properties Characteristic of Human Neurodegenerative Diseases.","authors":"Ethan D Smith, Giavanna Paterno, Brach M Bell, Kimberly-Marie M Gorion, Stefan Prokop, Benoit I Giasson","doi":"10.1007/s12017-025-08850-4","DOIUrl":"10.1007/s12017-025-08850-4","url":null,"abstract":"<p><p>Tauopathies, including Alzheimer's disease and frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17), are characterized by the aberrant aggregation of tau protein into neurofibrillary tangles. Despite extensive studies on tau aggregation, the mechanisms of tau misfolding and propagation remain incompletely understood. In this study, we utilize the SPAM (S320F/P301S) tau transgenic mouse model, which expresses 0N4R human tau with two FTDP-17 mutations, to investigate the biochemical properties and seeding potential of misfolded tau from these mice. Sarkosyl extraction and ultracentrifugation were employed to isolate detergent-insoluble tau aggregates (SPAM-tau) from aged SPAM mice. These aggregates were then tested for their prion-type seeding activity in an established HEK293T cell model comparing the induced aggregation of wild-type and mutant forms of human and murine tau. Our results show that SPAM-tau exhibits distinct and vigorous prion-like seeding properties, inducing the aggregation of human and murine tau homologues with the formation of amyloidogenic (Thioflavin S-positive) inclusions. Importantly, SPAM-tau aggregates can facilitate the prion-type misfolding of wild-type and mutant forms of human and mouse tau. We demonstrated that these induced tau aggregates are able to be further transmitted in passaging studies. Furthermore, SPAM-tau preferentially templated 4R tau isoforms, sharing strain-like seeding properties with insoluble tau derived from the brains of individuals with progressive supranuclear palsy (PSP-tau). In summary, these findings enhance our understanding of tau aggregation and propagation, suggesting that SPAM-tau may serve as a valuable tool for studying tauopathies and evaluating potential therapeutic strategies aimed at halting tau misfolding and propagation.</p>","PeriodicalId":19304,"journal":{"name":"NeuroMolecular Medicine","volume":"27 1","pages":"44"},"PeriodicalIF":3.3,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12125038/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144187456","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular Determinants of A9 Dopaminergic Neurons.","authors":"Abhishek Kumar Mishra, Shreya Dixit, Akanksha Singh, Toyaj Shukla, Syed Ibrahim Rizvi","doi":"10.1007/s12017-025-08861-1","DOIUrl":"10.1007/s12017-025-08861-1","url":null,"abstract":"<p><p>In the human brain, the nigrostriatal pathway regulates motor functions, and its selective deterioration leads to the onset of Parkinson's disease (PD), a neurodegenerative disorder characterized by motor dysfunction and significant disability. The A9 neurons, a subgroup of ventral mesencephalic dopaminergic (DA) neurons, form the nigrostriatal pathway that emerges from the nigral region and innervates into the striatum. These DA neurons exhibit extensive and arborized axonal terminals projecting into the dorsal striatum. This review examines the distinct molecular determinants underlying the development, projection pattern, survival, maintenance, and vulnerability of A9 neurons, distinguishing them from other ventral midbrain DA subgroups such as A8 and A10. Key transcription factors (e.g., Lmx1a/b, FoxA2, Pitx3), signaling cascade pathways (e.g., Sonic Hedgehog, Wnt/β-catenin), and molecular markers (e.g., Aldh1a1, GIRK2, ANT2) are discussed in detail. A comparative assessment of the electrophysiology, cytoarchitecture, energy demand, and antioxidant reserves of A9 DA neurons versus the neighboring ventral mesencephalic DA subgroups elucidates the role of intrinsic determinants in susceptibility and selective degeneration in PD. The unique susceptibility of A9 cells to redox imbalance, neuronal inflammation, and mitochondrial dysfunction is also explored. Furthermore, recent advancements in stem cell-based approaches for generating A9-like neurons and their application in cell transplantation therapies for PD are discussed. Current challenges, including integration and long-term survival of transplanted neurons, are highlighted alongside prospects of cell replacement therapy. By evaluating the molecular biology of A9 neurons, this review aims to understand PD pathology and develop strategies for novel therapeutic approaches.</p>","PeriodicalId":19304,"journal":{"name":"NeuroMolecular Medicine","volume":"27 1","pages":"43"},"PeriodicalIF":3.3,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144111467","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deregulation of Neuroinflammatory and Neurotrophic Factors as Biological Events Triggered by D-Galactose Chronic Administration in Wistar Rats.","authors":"Eduarda Behenck Medeiros, Sabrina da Silva, Francielle Mina, Adrielly Vargas Lidio, Amanda Boaventura, Laura Ceolin de Jesus, Michelle Lima Garcez, Gabriel Casagrande Zabot, Gabriela Piovesan Fenilli, Matheus Scarpatto Rodrigues, Jade de Oliveira, Samira S Valvassori, Josiane Budni","doi":"10.1007/s12017-025-08846-0","DOIUrl":"10.1007/s12017-025-08846-0","url":null,"abstract":"<p><p>The chronic administration of D-galactose (D-gal) is widely used to model brain senescence in rodents. However, the effects of prolonged oral exposure of D-gal on the neuroinflammatory cytokines in rats remain poorly characterized. Therefore, we administered D-gal (100 mg/kg) in male Wistar rats aged 3-4 months, via oral gavage once a day for 1, 2, 4, 6, or 8 weeks. Cytokine and neurotrophin levels were analyzed using the ELISA method. D-gal administrations for 4, 6, and 8 weeks significantly increased interleukin -1β (IL-1β), tumor necrosis factor-alpha (TNF-α), and interleukin-4 (IL-4) levels in the frontal cortex and hippocampus. In addition, 4, 6, and 8 weeks of D-gal administration significantly increased interleukin-10 (IL-10) levels in the frontal cortex; however, in the hippocampus, only 6 and 8 weeks of D-gal administration significantly increased the IL-10 levels. In terms of neurotrophin levels, our results demonstrated that 1 week of D-gal administration significantly increased Brain-derived Neurotrophic Factor (BDNF) and Nerve Growth Factor (NGF) in the hippocampus. In the frontal cortex, D-gal increased BDNF levels when administered for 1 and 2 weeks and increased NGF levels when administered for only 2 weeks. However, we observed a reduction of BDNF, NGF, and Glial cell line-derived Neurotrophic Factor (GDNF) levels after 6 and 8 weeks of D-gal treatment in the frontal cortex. Moreover, GDNF levels also were reduced after 4 weeks of D-gal administration. These findings suggest that oral D-gal exposure disrupts the balance of cytokines and neurotrophins, which may be an essential mechanism in brain aging and neurodegenerative processes.</p>","PeriodicalId":19304,"journal":{"name":"NeuroMolecular Medicine","volume":"27 1","pages":"41"},"PeriodicalIF":3.3,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144111327","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Protective Effect of the LRRK2 Kinase Inhibition in Human Fibroblasts Bearing the Genetic Variant GBA1 K198E: Implications for Parkinson's Disease.","authors":"Laura Patricia Perez-Abshana, Miguel Mendivil-Perez, Carlos Velez-Pardo, Marlene Jimenez-Del-Rio","doi":"10.1007/s12017-025-08864-y","DOIUrl":"10.1007/s12017-025-08864-y","url":null,"abstract":"<p><p>Parkinson's disease (PD) is a chronic and progressive neurodegenerative disorder for which there are currently no curative therapies. Therefore, the need for innovative treatments for this illness is critical. The glucosylceramidase beta 1 (GBA1) and leucine-rich repeated kinase 2 (LRRK2) genes have been postulated as potential genetically defined drug targets. We report for the first time that the LRRK2 inhibitor PF-06447475 (PF-475) not only restores GCase enzyme activity, but also increases mitochondrial membrane potential, significantly decreases DJ-1 Cys106-SO₃, reduces lysosome accumulation, and diminishes cleaved caspase-3 (CC3) in GBA1 K198E fibroblasts. Furthermore, in addition to a significant reduction in p-Ser935 LRRK2 kinase, we found that PF-475 reduced p-Thr73 RAB 10 and p-Ser129 α-Syn in mutant skin fibroblasts. In addition, we found that the GCase activator GCA (NCGC00188758) increased GCase activity and decreased lysosomal accumulation, but did not affect p-Ser935 LRRK2, ∆Ψm, p-Ser129 α-Syn, DJ-1 Cys106-SO₃, or CC3 in K198E GBA1 fibroblasts. The GCase inhibitor conduritol-β-epoxide (CBE), used as an internal control, significantly reduced GCase and left the other pathological markers largely unaltered in GBA1 K198E, but reduced GCase and increased the accumulation of lysosomes only in WT GBA1 fibroblasts. Taken together, these results suggest that LRRK2 is a critical signaling kinase in the pathogenic mechanism associated with the lysosomal GBA1/GCase K198E variant. Our findings suggest that the use of LRRK2 inhibitors in PD patients with GBA1 mutations, such as K198E, may be effective in reversing GBA1/GCase deficiency, autophagy impairment, oxidative stress, and neuronal death.</p>","PeriodicalId":19304,"journal":{"name":"NeuroMolecular Medicine","volume":"27 1","pages":"42"},"PeriodicalIF":3.3,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12095415/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144111468","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hydro-Alcoholic Extract of Cynodon dactylon Ameliorates Malathion-Induced Neurocognitive Behavior and Neurotoxicity.","authors":"Divyansh Sharma, Sakshi Mishra, Gaurav Jha, Bhawna Tomar, Sonam Kanchan, Radhika Kapoor, Sushma, Shivangi Gupta, Shubha Shukla, Srikanta Kumar Rath","doi":"10.1007/s12017-025-08859-9","DOIUrl":"10.1007/s12017-025-08859-9","url":null,"abstract":"<p><p>Organophosphate insecticides like malathion, though less toxic than other compounds in the same class, remain a significant public health concern due to their widespread use and potential neurotoxic effects. Prolonged exposure to malathion can lead to environmental contamination and neurobehavioral issues such as anxiety, depression, and cognitive impairment, mediated through cholinergic and non-cholinergic pathways. Cynodon dactylon (L.), a medicinal herb renowned in traditional and Ayurvedic medicine, exhibits anti-inflammatory, antioxidant, anti-diabetic, and neuroprotective properties. Evidence suggests that it can mitigate neurotoxicity and improve brain antioxidant status in rodent models. Therefore, this study explored the protective effects of the hydro-alcoholic extract of Cynodon dactylon (HAECD) on malathion-induced neurotoxicity, emphasizing its impact on behavior, biochemistry, and brain structure. Forty-two Swiss mice were randomly assigned to six groups, each containing seven mice. One group received normal saline (control), while another was given malathion (100 mg/kg, orally). Three groups received HAECD (250, 500, or 1000 mg/kg daily) alongside malathion, and the final group received only HAECD (1000 mg/kg, orally). Behavioral tests, including the elevated plus maze, light-dark test, and Morris water maze to assess the anxiety-depression-like behaviors, and cognitive function. Biochemical analyses measured acetylcholinesterase activity, lipid peroxidation, antioxidant enzymes (superoxide dismutase and catalase), and brain-derived neurotrophic factor (BDNF). Inflammatory markers and hippocampal histopathology were also examined. Results indicated that HAECD significantly alleviated anxiety and cognitive dysfunction while reducing oxidative stress markers, restoring antioxidant enzyme levels, and modulating brain-derived neurotrophic factor and inflammatory responses. These findings highlight the potential of HAECD in protecting the brain from malathion-induced neurotoxicity.</p>","PeriodicalId":19304,"journal":{"name":"NeuroMolecular Medicine","volume":"27 1","pages":"39"},"PeriodicalIF":3.3,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144111465","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Improvement of Parkinson's Disease Symptoms by Butylphthalide Through Modulation of Microglial Activation.","authors":"Xue Wang, Huimin Shi, Zibin Wei, Ping Liu, Shujuan Tian, Xueqin Song","doi":"10.1007/s12017-025-08865-x","DOIUrl":"10.1007/s12017-025-08865-x","url":null,"abstract":"<p><p>Microglia-mediated neuroinflammation plays an important role in the pathogenesis of Parkinson's disease (PD). Studies have shown that butylphthalide (3-n-butylphthalide or NBP) can play an anti-inflammatory role in other diseases by regulating the activation of microglia. This study investigates the neuroprotective and anti-inflammatory effects of NBP in a mouse model of Parkinson's disease (PD) induced by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The primary aim was to determine whether NBP can improve symptoms of PD by modulating microglial activation and to explore the underlying mechanisms involved. Motor function (assessed via Open Field and Pole Climbing tests), dopaminergic neuronal loss, and activation of different microglial subtypes were assessed in control, MPTP-treated, and NBP + MPTP-treated mice. A p38 phosphorylation inhibitor + MPTP group was also established to investigate potential mechanisms of NBP action. Mice treated with NBP exhibited significantly improved motor function and reduced dopaminergic neuronal loss compared to MPTP-treated mice. In PD mice, pro-inflammatory factor expression was elevated, anti-inflammatory factor expression was reduced, and the expression of arginase-1 (arg-1), a marker for M2 microglia, was decreased. NBP treatment resulted in reduced levels of pro-inflammatory factors, increased levels of anti-inflammatory factors, and elevated arg-1 expression. Additionally, inhibition of p38 phosphorylation further decreased pro-inflammatory factor expression while increasing both anti-inflammatory factor levels and arg-1 expression. The findings indicate that NBP regulates neuroinflammation and improves symptoms of PD by promoting the transformation of microglia to the M2 phenotype, likely mediated through the p38 phosphorylation pathway.</p>","PeriodicalId":19304,"journal":{"name":"NeuroMolecular Medicine","volume":"27 1","pages":"40"},"PeriodicalIF":3.3,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144111466","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring Proteomic Alterations in Intellectual Disability: Insights from Hyperlipidemia and Hyperphosphatasia Subgroups.","authors":"Soma Vankwani, Munazza Raza Mirza, Muhammad Tahir, Muhammad Wasim, Sajid Ali Rajput, Haq Nawaz Khan, Martin R Larsen, Muhammad Iqbal Choudhary, Fazli Rabbi Awan","doi":"10.1007/s12017-025-08855-z","DOIUrl":"10.1007/s12017-025-08855-z","url":null,"abstract":"<p><p>A significant increase of neurodevelopment disorders (NDDs) among children presents growing healthcare challenge worldwide. Owing to heterogenic, multifactorial nature of NDDs, understanding pathophysiology of disease, finding effective methods for the early detection and intervention of NDDs has become extremely complex. This study aims to investigate the molecular mechanisms of NDDs, focusing on the associations between hyperphosphatasia (HPP) and hyperlipidemia (HLD) in patients with intellectual disability (ID). Blood samples from 800 study participants (ID patients and healthy individuals, HC) were analyzed for the biochemical differences. Among them, 105 ID patients with uniquely altered biochemical profiles (ID-HPP, n = 28; ID-HLD, n = 77) and 65 HC samples were further investigated for nLC-MS/MS-based proteomic analysis. A total of 354 proteins were identified in label-free quantitative proteomic analysis of the all groups (ID-HPP, ID-HLD, and HC). The ID-HPP and ID-HLD groups each had distinct protein profiles compared to HC, with 28 and 85 differentially expressed proteins, respectively. The ID-HLD group had 66 unique proteins, whereas ID-HPP had 9 unique proteins, with 19 proteins common among the subgroups of ID. Pathway analysis of common proteins revealed shared pathways as the complement system and lipoprotein metabolism disruptions, but distinct pathway disturbances: toll-like receptor and integrin signaling in ID-HPP, and hemostatic pathway dysregulation in ID-HLD. These findings elucidate systemic pathway abnormalities in NDDs, including ID.</p>","PeriodicalId":19304,"journal":{"name":"NeuroMolecular Medicine","volume":"27 1","pages":"38"},"PeriodicalIF":3.3,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144111464","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unlocking Alzheimer's Disease: The Role of BDNF Signaling in Neuropathology and Treatment.","authors":"Saad Misfer Alqahtani, Hayder M Al-Kuraishy, Ali I Al Gareeb, Ali K Albuhadily, Athanasios Alexiou, Marios Papadakis, Loah R Hemeda, Safaa A Faheem, Gaber El-Saber Batiha","doi":"10.1007/s12017-025-08857-x","DOIUrl":"10.1007/s12017-025-08857-x","url":null,"abstract":"<p><p>Alzheimer's disease (AD) remains one of the most debilitating neurodegenerative disorders, with its pathological hallmark being progressive cognitive decline and memory loss. Recent research has illuminated the crucial role of the brain-derived neurotrophic factor (BDNF) in the central nervous system (CNS), highlighting its impact on neurogenesis, synaptic plasticity, and neuronal survival. Dysregulation of the BDNF signaling axis, particularly the imbalance between its precursor form and mature BDNF, is strongly implicated in the pathophysiology of AD. This review explores the molecular mechanisms through which BDNF modulates AD neuropathology and presents novel therapeutic strategies to activate BDNF signaling. We focus on the potential of BDNF activators, such as TrkB agonists and mimetic molecules, to restore synaptic function and ameliorate cognitive deficits in AD. Furthermore, we examine the challenges in translating these findings into clinical practice, including issues with blood-brain barrier penetration and the need for precise receptor targeting. The review emphasizes the therapeutic potential of repurposed drugs, including statins and metformin, in enhancing BDNF signaling and offers new insights into the future of AD treatment. Ultimately, this work provides a compelling argument for BDNF-based therapies as a promising avenue for mitigating the cognitive decline associated with Alzheimer's disease, signaling a hopeful direction for future research and clinical trials.</p>","PeriodicalId":19304,"journal":{"name":"NeuroMolecular Medicine","volume":"27 1","pages":"36"},"PeriodicalIF":3.3,"publicationDate":"2025-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12084274/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144086628","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Electro-Acupuncture Therapy Alleviates Post-Stroke Insomnia by Regulating Sirt1 and the Nrf2-ARE Pathway.","authors":"Yiming Wang, Yifei Chen, Jianbo Yang, Wei Sun, Xiaoning Zhang","doi":"10.1007/s12017-025-08862-0","DOIUrl":"https://doi.org/10.1007/s12017-025-08862-0","url":null,"abstract":"<p><p>Post-stroke insomnia (PSI) is a common complication following stroke, which seriously affects patients' life quality. Electro-acupuncture (EA) is an innovative form of traditional Chinese acupuncture that combines electricity with needles to achieve the prevention and treatment of diseases. However, there is limited understanding regarding the treatment mechanism of EA in PSI. In our study, we aimed to investigate the role of EA on PSI development. Our study findings indicated that the quality of sleep, levels of neurotransmitters 5-hydroxytryptamine (5-HT) and gamma-aminobutyric acid (γ-GABA), and antioxidant levels showed significant improvement following EA treatment in PSI clinical samples and rat models, while the levels of pro-inflammatory factor interleukin 6 (IL-6), tumor necrosis factor-alpha (TNF-α), and astrocyte damage were notably reduced. Furthermore, it was discovered that the levels of sirtuin 1 (Sirt1) were reduced in PSI, a condition that was significantly ameliorated by EA treatment. Additionally, the inhibition of Sirt1 caused a marked elevation in astrocyte apoptosis, inflammatory response, and oxidative stress. Besides, the nuclear factor E2-related factor 2 (Nrf2)-antioxidant response element (ARE) pathway was deactivated in the PSI rat model and Sirt1-silenced cells. However, the suppressive impact was successfully counteracted by EA or estazolam (ES), and the overexpression of Nrf2 partially alleviated the increase in apoptosis, inflammation, and oxidative stress caused by Sirt1 knockdown. Taken together, these findings indicated that EA improved sleep quality and silenced Sirt1-induced apoptosis, inflammation, and oxidative stress in PSI by activating the Nrf2-ARE pathway.</p>","PeriodicalId":19304,"journal":{"name":"NeuroMolecular Medicine","volume":"27 1","pages":"37"},"PeriodicalIF":3.3,"publicationDate":"2025-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144086610","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Conceivable Role of Metabolic Syndrome in the Pathogenesis of Alzheimer's Disease: Cellular and Subcellular Alterations in Underpinning a Tale of Two.","authors":"Ekremah A Alzarea, Hayder M Al-Kuraishy, Ali I Al-Gareeb, Athanasios Alexiou, Marios Papadakis, Olivia N Beshay, Gaber El-Saber Batiha","doi":"10.1007/s12017-025-08832-6","DOIUrl":"10.1007/s12017-025-08832-6","url":null,"abstract":"<p><p>Alzheimer's disease (AD)is an age-related neurodegenerative disease characterized by memory decline and cognitive impairment .AD is common in people aged > 65 years, though most of AD cases are sporadic, which accounts for 95%, and 1-5% of AD is caused by familial causes . The causes of AD are aging, environmental toxins, and cardiometabolic factors that induce the degeneration of cholinergic neurons. It has been shown that the metabolic syndrome which is a clustering of dissimilar constituents including insulin resistance (IR), glucose intolerance, visceral obesity, hypertension, and dyslipidemia is implicated in the pathogenesis of AD. Metabolic syndrome disapprovingly affects cognitive function and the development in AD by inducing the development of oxidative stress, neuroinflammation, and brain IR. These changes, together with brain IR, impair cerebrovascular reactivity causing cognitive impairment and dementia. Nevertheless, the fundamental mechanism by which metabolic syndrome persuades AD risk is not entirely explicated. Accordingly, this review aims to discuss the connotation between metabolic syndrome and AD. In conclusion, metabolic syndrome is regarded as a possible risk factor for the initiation of AD neuropathology by diverse signaling pathways such as brain IR, activation of inflammatory signaling pathways, neuroinflammation, defective proteostasis, and dysregulation of lipid mediators.</p>","PeriodicalId":19304,"journal":{"name":"NeuroMolecular Medicine","volume":"27 1","pages":"35"},"PeriodicalIF":3.3,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12084261/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144086627","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}