Frontiers in Aging Neuroscience最新文献

{"title":"Age-sex differences in Alzheimer's and related dementias burden and risk factors in east and Southeast Asia: results from the 2021 GBD study.","authors":"Tengyu Zhao, Pengyu Pan, Yuhan Zhou, Xinyue Zhang, Quan Li, Yanyan Zhou","doi":"10.3389/fnagi.2025.1562148","DOIUrl":"10.3389/fnagi.2025.1562148","url":null,"abstract":"<p><strong>Background: </strong>Alzheimer's disease and related dementias (ADRD) significant global public health challenges, leading to severe disability in patients and placing a heavy burden on caregivers. However, epidemiological studies focusing on ADRD in specific regions remain limited. This study aims to comprehensively analyze and describe the current status and changing trends of ADRD in Non-High-income East Asia (NHIEA), Non-High-income Southeast Asia (NHISEA), and High-income Asia Pacific (HIAP), providing more detailed real-world data to inform policymaking.</p><p><strong>Methods: </strong>The data for ADRD used in this study were extracted from the 2021 Global Burden of Disease (GBD) database. We employed three major indicators of disease burden-prevalence, incidence, and years lived with disability (YLD)-and explored associated risk factors, further analyzing trends by age and sex. The results are presented as mean values with 95% uncertainty intervals (UIs). Additionally, we explored the differences between NHIEA, NHISEA, HIAP and other regions, as well as the potential associations between the disease burden of Alzheimer's and other dementias and socioeconomic factors.</p><p><strong>Results: </strong>The findings indicate that the burden of dementia is rising in East and Southeast Asia, with women showing a higher burden across all indicators. Notably, in NHIEA, particularly in China, the burden of dementia has increased with the rising Social Demographic Index (SDI). China experienced a 27.3% increase in Alzheimer's disease and other dementia ASYRs from 1990 to 2021, with a sharp 7.6% annual surge in 2021 alone, outpacing regional averages. Gender analysis revealed that women bear a disproportionate burden of Alzheimer's disease and related dementias, especially after menopause, when the risk increases significantly. The study also identified smoking, high blood sugar, and high body mass index as important risk factors affecting the disease burden. The contribution of these risk factors varies across regions, genders, and age groups.</p><p><strong>Conclusion: </strong>The health burden of ADRD remains substantial, with distinct patterns observed across NHIEA, NHISEA, and HIAP, including regional variations in gender, age, and risk factors. These findings highlight the need for tailored approaches to allocate healthcare resources and implement appropriate control measures based on the specific conditions of each region to address this growing public health challenge. Future research should prioritize comparative analyses across continents and within regions to inform the development of more region-specific prevention strategies for ADRD.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"17 ","pages":"1562148"},"PeriodicalIF":4.1,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12245908/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144625867","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Editorial: Advances in Parkinson's Disease Research: Exploring Biomarkers and Therapeutic Strategies for Halting Disease Progression.","authors":"Anastasia Bougea, Yildiz Degirmenci","doi":"10.3389/fnagi.2025.1640566","DOIUrl":"10.3389/fnagi.2025.1640566","url":null,"abstract":"","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"17 ","pages":"1640566"},"PeriodicalIF":4.1,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12245866/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144625868","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metformin improves age-related visual cortex dysfunction in mice by reducing noise correlation in the primary visual cortex.","authors":"Xiaoming Liu, Yifeng Zhou, Jiachen Liu, Guangwei Xu","doi":"10.3389/fnagi.2025.1572653","DOIUrl":"10.3389/fnagi.2025.1572653","url":null,"abstract":"<p><strong>Introduction: </strong>Age-related decline in visual processing has been observed in association with reduced orientation selectivity and decreased signal-to-noise ratios in the primary visual cortex (V1). Elevated noise correlations between neurons are associated with impaired visual discrimination in aging; however, less is known about therapeutic interventions that could preserve visual cortical function during aging. In this study, we investigated the effects of metformin treatment on age-related changes in visual processing and neuronal correlations in V1.</p><p><strong>Methods: </strong>We conducted <i>in vivo</i> electrophysiological recordings to investigate whether 3 weeks of acute gavage with metformin improves visual processing in 12-month-old mice compared to 8-week-old mice by modulating neural noise in the V1, and used western blot analysis to investigate the molecular mechanism of the effect of metformin.</p><p><strong>Results: </strong><i>In vivo</i> electrophysiological recordings revealed that aging led to V1 neuronal hyperactivity, accompanied by reduced orientation selectivity, a decreased signal-to-noise ratio, and increased response variability. Notably, aged mice exhibited increased noise correlation, response covariance, and population variability. Analysis of fast-spiking interneurons revealed impaired noise suppression in the inhibitory circuits of aged mice. Daily metformin treatment reversed these age-related alterations by improving fast-spiking neuron-mediated decorrelation and reducing noise correlation. Mechanistically, metformin upregulated the protein expression levels of glutamic acid decarboxylase 67 and gephyrin, key components of inhibitory synapses, suggesting that metformin enhances visual processing by strengthening inhibitory signaling and reducing the correlated variability in the V1.</p><p><strong>Discussion: </strong>Metformin treatment effectively ameliorated these deficits through enhanced GABAergic signaling; however, the broader therapeutic mechanisms across sensory systems remain unclear. In this study, we demonstrate that metformin preserves visual function by restoring excitatory-inhibitory balance, suggesting a promising approach for age-related sensory decline.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"17 ","pages":"1572653"},"PeriodicalIF":4.1,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12241007/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144607961","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reduced synaptic tagging by complement protein C3 is associated with elevated extracellular matrix in the middle-aged cerebellum of mice.","authors":"Henning Peter Düsedau, Carla Cangalaya, Stoyan Stoyanov, Alexander Dityatev, Ildiko Rita Dunay","doi":"10.3389/fnagi.2025.1616390","DOIUrl":"10.3389/fnagi.2025.1616390","url":null,"abstract":"<p><strong>Background: </strong>Aging of the brain is associated with cognitive decline and recognized as a major risk factor for the development of neurodegenerative diseases. On a cellular level, brain aging is accompanied by a progressive increase of the basal pro-inflammatory tonus, leading to the activation of phagocytic pathways in brain-resident microglia and disruptive effects on synaptic neurotransmission. While the aging process affects all brain compartments at different velocities and one of the particularly affected regions is the cerebellum (CB), the underlying effects remain elusive.</p><p><strong>Methods: </strong>In the present study, we harnessed a murine model of natural aging in males combined with orthogonal experimental approaches comprising of cytokine gene expression analysis, flow cytometry, immunohistochemistry, and flow synaptometry.</p><p><strong>Results: </strong>We report age-dependent morphological and phenotypic changes in microglia that are distinct in the cortex (CTX) and CB. Furthermore, we show an increased expression of cytokines and complement factors upon aging and a decline of C3-tagged VGLUT1⁺ presynaptic puncta in the CB. Using flow synaptometry to quantify the composition of synapses in more detail, we validated the reduction of C3b-labeled excitatory synaptosomes while the overall frequency of glutamatergic synaptosomes remained unaffected by aging. Notably, proteoglycans brevican and aggrecan, key components of the neural extracellular matrix, were significantly upregulated in the middle-aged CB.</p><p><strong>Discussion: </strong>The data presented herein suggests the ECM-mediated shielding of synapses from complement-tagging and subsequent engulfment by microglia. Thus, we provide novel insights into mechanisms that may confer resilience in the brain by modulating synapse removal in the context of aging.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"17 ","pages":"1616390"},"PeriodicalIF":4.1,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12240999/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144607962","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Regional network covariance patterns of white matter integrity related to cardiorespiratory fitness in healthy aging.","authors":"Samantha G Smith, Pradyumna K Bharadwaj, David A Raichlen, Matthew D Grilli, Jessica R Andrews-Hanna, Georg A Hishaw, Matthew J Huentelman, Theodore P Trouard, Gene E Alexander","doi":"10.3389/fnagi.2025.1542458","DOIUrl":"10.3389/fnagi.2025.1542458","url":null,"abstract":"<p><p>Cardiorespiratory fitness (CRF), measured by VO₂max, is an indicator of vascular functioning that can influence the integrity of brain microstructural white matter tracts in aging. How CRF is related to regional patterns of white matter bundles for magnetic resonance imaging (MRI) diffusion metrics (axial diffusivity, AD; radial diffusivity, RD; mean diffusivity, MD; fractional anisotropy, FA) has been less studied. We used a multivariate analysis method, the Scaled Subprofile Model (SSM), to identify network patterns of MRI tract-specific white matter integrity (WMI) for AD, RD, MD, and FA related to VO₂max and to evaluate their relation to demographic, vascular health, and dementia risk factors in 167 cognitively unimpaired older adults, ages 50 to 88. We identified four CRF-related regional patterns of WMI characterized by enhanced integrity in commissural pathways that connect areas within anterior brain regions (prefrontal body of the corpus callosum), connect subcortical regions to one another (fornix), and include selected association tracts (arcuate fasciculus, superior longitudinal fasciculus). Greater white matter lesion load, in addition to age, was associated with reduced expression of all four CRF-WMI patterns, while high vascular risk level was further associated with reduced expression of the RD, MD, and FA patterns. The regional patterns of RD and FA were most strongly associated with CRF. The results suggest that in healthy older adults, enhanced CRF is differentially associated with regional patterns of WMI, which are related to age and further impacted by macrostructural white matter lesion load and vascular risk. These findings support the use of the multivariate SSM in identifying regional patterns of white matter tracts that may provide markers of brain aging and cerebrovascular health.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"17 ","pages":"1542458"},"PeriodicalIF":4.1,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12241056/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144607963","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Necroptosis in vascular cognitive impairment: mechanisms and therapeutic potential.","authors":"Shufei Wei, Lin Cheng, Chunxiao Shen, Zefen Li, Jiahui Teng, Liangliang Wang, Xiaorong Zhang","doi":"10.3389/fnagi.2025.1599773","DOIUrl":"10.3389/fnagi.2025.1599773","url":null,"abstract":"<p><p>Cerebral ischemia and hypoxia play key roles in the occurrence and development of vascular cognitive impairment (VCI). However, the pathophysiology of VCI remains unclear. Necroptosis is a non-cysteine-dependent form of cell death mediated by serine/threonine kinases receptor-interacting protein kinase-1 and -3 and mixed lineage kinase domain-like protein. A search of PubMed and Web of Science was conducted using terms related to VCI and necroptosis. Necroptosis is important in neuroinflammation, neuronal loss, blood-brain barrier dysfunction, and demyelination. Cerebral ischemia activates the necroptotic pathway, and necroptosis inhibitors have a significant inhibitory effect on brain injury. This review focuses on the pathogenesis of VCI and clarifies the core regulatory mechanism of necroptosis in vascular dementia, which lays a scientific foundation for cognitive impairment prevention and treatment by targeting necroptosis in VCI.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"17 ","pages":"1599773"},"PeriodicalIF":4.1,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12237979/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144599880","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Modeling heterogeneity in cognitive trajectories in the Framingham Heart Study.","authors":"Yuan Fang, Jiachen Chen, Jesse Mez, Claudia L Satizabal, Michael L Alosco, Wei Qiao Qiu, Margaret F Doyle, Joanne M Murabito, Kathryn L Lunetta","doi":"10.3389/fnagi.2025.1471154","DOIUrl":"10.3389/fnagi.2025.1471154","url":null,"abstract":"<p><strong>Introduction: </strong>The prevalence of cognitive impairment in the population is growing; however, there is substantial heterogeneity in the rate of decline across different cognitive domains. Harmonized factor scores measuring memory, executive function, and language domains have been created in the Framingham Heart Study (FHS).</p><p><strong>Methods: </strong>This work identified FHS participants with two or more repeated factor scores after age 60 and fitted latent class mixed models (LCMM) to cluster cognitive trajectories within each domain. Non-linear shapes of trajectories were modeled piecewise linearly, followed by stepwise selections to select cluster-specific change points.</p><p><strong>Results: </strong>We identified different latent classes of participants with early cognitive decline, compared to late decliners, for each domain. Ten-fold cross-validation yielded stable subgroupings. Our findings show latent-class-related differential patterns in cognitive aging in the FHS. We also investigated the association between identified latent classes with existing protein biomarkers of cognitive aging in a subsample of the study and found elevated levels of CD40L and CD14 were associated with a higher risk of early decline in memory and executive function domain, respectively.</p><p><strong>Discussion: </strong>In summary, our study advances the understanding of cognitive decline heterogeneity among FHS participants and sets the stage for further investigations into early intervention strategies and personalized approaches to mitigate cognitive aging risks.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"17 ","pages":"1471154"},"PeriodicalIF":4.1,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12238755/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144599879","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Predicting amyloid status in mild cognitive impairment: the role of semantic intrusions combined with plasma biomarkers.","authors":"Yao Lu, Liang Cui, Lin Huang, Fang Xie, Qi-Hao Guo","doi":"10.3389/fnagi.2025.1624513","DOIUrl":"10.3389/fnagi.2025.1624513","url":null,"abstract":"<p><strong>Background: </strong>The efficacy of traditional semantic intrusion measurements in identifying amyloid deposition in mild cognitive impairment (MCI) patients remains suboptimal. It is anticipated that integrating innovative cognitive assessments with blood biomarker analyses will enhance the effectiveness of screening for Alzheimer's disease (AD).</p><p><strong>Methods: </strong>The research included 204 participants from the Chinese Preclinical Alzheimer's Disease Study cohort, assessed between March 2019 and February 2023. The Bi-list Verbal Learning Test (BVLT) was utilized to measure semantic intrusions, while amyloid burden was quantified using neuroimaging with 18F-florbetapir PET/CT scans. Additionally, the study analyzed Apolipoprotein E loci and plasma biomarkers, including Aβ42, Aβ40, Tau, p-tau181, p-tau217, Nfl, and GFAP.</p><p><strong>Results: </strong>The study revealed that semantic intrusion errors on the BVLT are highly predictive of amyloid deposition in MCI participants. Binary logistic regression analysis confirmed that semantic intrusion errors on the Bi-list Verbal Learning Test, along with p-tau217 levels and GFAP levels, can effectively predict amyloid positive MCI. Correlation analysis further established a positive association between p-tau217, GFAP, and semantic intrusion errors among patients with A+ MCI. The combined predictors (p-tau217, GFAP, semantic intrusion errors) demonstrated outstanding performance in ROC analysis, achieving an AUC of 0.964, with a sensitivity of 92.7% and a specificity of 85.7%.</p><p><strong>Conclusion: </strong>The study suggests that semantic intrusion errors from the BVLT, along with plasma biomarkers p-tau217 and GFAP, may serve as sensitive indicators for AD-related MCI. Combining these biomarkers with semantic intrusion errors offers a strong predictive model for assessing amyloid status in MCI patients.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"17 ","pages":"1624513"},"PeriodicalIF":4.1,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12237882/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144599881","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Voxel- and surface-based morphometry in the cortical thickness and cortical and subcortical gray matter volume in patients with mild-to-moderate Alzheimer's disease.","authors":"Kaidi Li, Dingling Xie, Zhengyong Zhang, Chunyu Fu, Chunyang Li","doi":"10.3389/fnagi.2025.1546977","DOIUrl":"10.3389/fnagi.2025.1546977","url":null,"abstract":"<p><strong>Aim: </strong>This study aimed to investigate alterations in whole-brain cortical thickness (CT) and cortical and subcortical gray matter volume (GMV) in patients with Alzheimer's disease (AD) compared with healthy controls (HC) using voxel-based morphometry (VBM) and surface-based morphometry (SBM). Furthermore, we sought to develop a combined predictive model based on these neuroimaging markers and assess their potential clinical utility for the early detection and diagnosis of AD.</p><p><strong>Methods: </strong>A total of 42 patients diagnosed with mild-to-moderate AD and 49 demographically matched HC were recruited for this study. VBM and SBM analyses were performed on three-dimensional T1-weighted magnetization-prepared rapid gradient echo (3D T1-MPRAGE) imaging sequences to identify brain regions that exhibited statistically significant differences between the AD and HC groups. Brain regions showing significant group differences were selected as the regions of interest (ROIs). Pearson's correlation analysis was used to assess the relationship between extracted neuroimaging metrics (CT, cortical GMV, and subcortical GMV) and cognitive performance. Predictive models were constructed using CT (from SBM), cortical GMV, and subcortical GMV (from VBM) metrics derived from ROIs, both individually and in combination. Model performance in discriminating between patients with AD and HCs was evaluated using a receiver operating characteristic (ROC) curve analysis.</p><p><strong>Results: </strong>Compared to HCs, patients with AD exhibited significant CT reductions primarily in the transverse temporal gyrus, superior temporal gyrus, supramarginal gyrus, insula, temporal pole, entorhinal cortex, and fusiform gyrus. Significant GMV reductions in patients with AD were observed predominantly in the hippocampus, parahippocampal gyrus, posterior temporal lobe, inferior temporal gyrus, middle temporal gyrus, limbic lobe structures, fusiform gyrus, amygdala, and thalamus, as detected by VBM analysis. Extracted CT, cortical GMV, and subcortical GMV measurements from the ROIs demonstrated significant positive correlations with both MMSE and MoCA scores.</p><p><strong>Conclusion: </strong>In patients with AD, VBM and SBM showed overlapping cortical GMV and CT reductions. Volume/thickness reduction was correlated with lower MMSE/MoCA scores, confirming functional relevance. ROC analysis revealed that combining CT and GMV improved cognitive impairment prediction compared to single measures. This integrated approach may enhance clinical diagnosis and early risk identification of AD.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"17 ","pages":"1546977"},"PeriodicalIF":4.1,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12238721/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144599882","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A new pathway for neuroprotection against tau hyperphosphorylation via δ-opioid receptor initiated inhibition of CDK5 and AMPK signaling.","authors":"Jiahui Li, Yuan Xu, Gianfranco Balboni, Ying Xia","doi":"10.3389/fnagi.2025.1587219","DOIUrl":"10.3389/fnagi.2025.1587219","url":null,"abstract":"<p><strong>Introduction: </strong>Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by decreased memory and cognitive impairment. Abnormal tau hyperphosphorylation ultimately forms neurofibrillary tangles, which is one of the most important pathological features of AD. Since we have previously shown that the δ-opioid receptor (DOR) is neuroprotective in the brain, we asked if DOR plays any role in the control of tauopathy.</p><p><strong>Methods: </strong>In the PC12 cell model with okadaic acid-induced tau hyperphosphorylation, cell viability and cytotoxicity were evaluated by using CCK8 assay kit and lactate dehydrogenase cytotoxicity assay kit. The techniques of western blot and immunofluorescence were used to investigate the effect of DOR on tau hyperphosphorylation.</p><p><strong>Results: </strong>We found that DOR activation inhibited okadaic acid-induced tau hyperphosphorylation in PC12 cells and attenuated the cell cycle reactivation and apoptosis. The DOR effect was blocked by Naltrindole, a DOR antagonist. Furthermore, the mechanistic studies showed that the DOR displayed its effect by reducing the expression of cyclin-dependent kinase (CDK) 5 and AMP-activated protein kinase (AMPK) in the model of tauopathy.</p><p><strong>Discussion: </strong>Our novel findings suggest that DOR signaling may protect neurons from AD injury by inhibiting tau hyperphosphorylation.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"17 ","pages":"1587219"},"PeriodicalIF":4.1,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12236099/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144590830","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}