Pub Date : 2024-07-16DOI: 10.3389/fnagi.2024.1339163
Qiong-Yao Li, Yan Fu, Xin-Jing Cui, Zuo-teng Wang, Lan Tan
This study aimed to investigate the cognitive profile and prospective cognitive changes in non-demented adults with elevated Modified Dementia Risk Scores (MDRS), while also exploring the potential relationship between these associations and cerebrospinal fluid (CSF) biomarkers of Alzheimer’s disease (AD) pathology and neuroinflammation.Within the Chinese Alzheimer’s Biomarker and LifestylE (CABLE) database, 994 participants without dementia were assessed on MDRS, CSF biomarkers and cognition. We examined the associations of the MDRS with CSF biomarkers and cognitive scores using linear regressions. Causal mediation analyses were conducted to analyze the associations among MDRS, brain pathologies, and cognition. The Alzheimer’s Disease Neuroimaging Initiative (ADNI) study was used to validate the mediation effects and to investigate the longitudinal association between MDRS and cognitive decline.The results revealed that higher MDRS were linked to poorer cognitive performance (Model 1: PFDR < 0.001; Model 2: PFDR < 0.001) and increases in CSF levels of phosphorylated tau (P-tau, Model 1: PFDR < 0.001; Model 2: PFDR < 0.001), total tau (T-tau, Model 1: PFDR < 0.001; Model 2: PFDR < 0.001), P-tau/Aβ42 ratio (Model 1: PFDR = 0.023; Model 2: PFDR = 0.028), T-tau/Aβ42 ratio (Model 1: PFDR < 0.001; Model 2: PFDR < 0.001) and soluble triggering receptor expressed on myeloid cells 2 (sTrem2, Model 1: PFDR < 0.001; Model 2: PFDR < 0.001) in the CABLE study. The impact of MDRS on cognition was partially mediated by neuroinflammation and tau pathology. These mediation effects were replicated in the ADNI study. Baseline MDRS were significantly associated with future cognitive decline, as indicated by lower scores on the Mini-Mental State Examination (MMSE, Model 1: PFDR = 0.045; Model 2: PFDR < 0.001), ADNI composite memory score (ADNI-MEM, Model 1: PFDR = 0.005; Model 2: PFDR < 0.001), ADNI composite executive function score (ADNI-EF, Model 1: PFDR = 0.045; Model 2: PFDR < 0.001), and higher score on the Alzheimer’s Disease Assessment Scale (ADAS13, Model 1: PFDR = 0.045; Model 2: PFDR < 0.001).The findings of this study revealed significant associations between MDRS and cognitive decline, suggesting a potential role of tau pathology and neuroinflammation in the link between MDRS and poorer cognitive performance in individuals without dementia. Consequently, the MDRS holds promise as a tool for targeted preventive interventions in individuals at high risk of cognitive impairment.
{"title":"Association of modified dementia risk score with cerebrospinal fluid biomarkers and cognition in adults without dementia","authors":"Qiong-Yao Li, Yan Fu, Xin-Jing Cui, Zuo-teng Wang, Lan Tan","doi":"10.3389/fnagi.2024.1339163","DOIUrl":"https://doi.org/10.3389/fnagi.2024.1339163","url":null,"abstract":"This study aimed to investigate the cognitive profile and prospective cognitive changes in non-demented adults with elevated Modified Dementia Risk Scores (MDRS), while also exploring the potential relationship between these associations and cerebrospinal fluid (CSF) biomarkers of Alzheimer’s disease (AD) pathology and neuroinflammation.Within the Chinese Alzheimer’s Biomarker and LifestylE (CABLE) database, 994 participants without dementia were assessed on MDRS, CSF biomarkers and cognition. We examined the associations of the MDRS with CSF biomarkers and cognitive scores using linear regressions. Causal mediation analyses were conducted to analyze the associations among MDRS, brain pathologies, and cognition. The Alzheimer’s Disease Neuroimaging Initiative (ADNI) study was used to validate the mediation effects and to investigate the longitudinal association between MDRS and cognitive decline.The results revealed that higher MDRS were linked to poorer cognitive performance (Model 1: PFDR < 0.001; Model 2: PFDR < 0.001) and increases in CSF levels of phosphorylated tau (P-tau, Model 1: PFDR < 0.001; Model 2: PFDR < 0.001), total tau (T-tau, Model 1: PFDR < 0.001; Model 2: PFDR < 0.001), P-tau/Aβ42 ratio (Model 1: PFDR = 0.023; Model 2: PFDR = 0.028), T-tau/Aβ42 ratio (Model 1: PFDR < 0.001; Model 2: PFDR < 0.001) and soluble triggering receptor expressed on myeloid cells 2 (sTrem2, Model 1: PFDR < 0.001; Model 2: PFDR < 0.001) in the CABLE study. The impact of MDRS on cognition was partially mediated by neuroinflammation and tau pathology. These mediation effects were replicated in the ADNI study. Baseline MDRS were significantly associated with future cognitive decline, as indicated by lower scores on the Mini-Mental State Examination (MMSE, Model 1: PFDR = 0.045; Model 2: PFDR < 0.001), ADNI composite memory score (ADNI-MEM, Model 1: PFDR = 0.005; Model 2: PFDR < 0.001), ADNI composite executive function score (ADNI-EF, Model 1: PFDR = 0.045; Model 2: PFDR < 0.001), and higher score on the Alzheimer’s Disease Assessment Scale (ADAS13, Model 1: PFDR = 0.045; Model 2: PFDR < 0.001).The findings of this study revealed significant associations between MDRS and cognitive decline, suggesting a potential role of tau pathology and neuroinflammation in the link between MDRS and poorer cognitive performance in individuals without dementia. Consequently, the MDRS holds promise as a tool for targeted preventive interventions in individuals at high risk of cognitive impairment.","PeriodicalId":503985,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"2 11","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141641202","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-15DOI: 10.3389/fnagi.2024.1421841
Wei Zheng, Ji He, Lu Chen, Weiyi Yu, Nan Zhang, Xiaoxuan Liu, D. Fan
Genetics have been shown to have a substantial impact on amyotrophic lateral sclerosis (ALS). The ALS process involves defects in axonal transport and cytoskeletal dynamics. It has been identified that KIF1A, responsible for encoding a kinesin-3 motor protein that carries synaptic vesicles, is considered a genetic predisposing factor for ALS.The analysis of whole-exome sequencing data from 1,068 patients was conducted to examine the genetic link between ALS and KIF1A. For patients with KIF1A gene mutations and a family history, we extended the analysis to their families and reanalyzed them using Sanger sequencing for cosegregation analysis.In our cohort, the KIF1A mutation frequency was 1.31% (14/1,068). Thirteen nonsynonymous variants were detected in 14 ALS patients. Consistent with the connection between KIF1A and ALS, the missense mutation p.A1083T (c.3247G>A) was shown to cosegregate with disease. The mutations related to ALS in our study were primarily located in the cargo-binding region at the C-terminal, as opposed to the mutations of motor domain at the N-terminal of KIF1A which were linked to hereditary peripheral neuropathy and spastic paraplegia. We observed high clinical heterogeneity in ALS patients with missense mutations in the KIF1A gene. KIF5A is a more frequent determinant of ALS in the European population, while KIF1A accounts for a similar proportion of ALS in both the European and Chinese populations.Our investigation revealed that mutations in the C-terminus of KIF1A could increase the risk of ALS, support the pathogenic role of KIF1A in ALS and expand the phenotypic and genetic spectrum of KIF1A-related ALS.
研究表明，遗传对肌萎缩性脊髓侧索硬化症（ALS）有重大影响。ALS 的发病过程涉及轴突运输和细胞骨架动力学的缺陷。研究人员对 1,068 名患者的全外显子组测序数据进行了分析，以研究 ALS 与 KIF1A 基因之间的遗传联系。对于有 KIF1A 基因突变和家族史的患者，我们将分析扩展到了他们的家族，并使用 Sanger 测序对他们进行了重新分析，以进行共分离分析。在14名ALS患者中检测到了13个非同义变异。与KIF1A和ALS之间的联系相一致的是，错义突变p.A1083T（c.3247G>A）被证明与疾病共聚集。在我们的研究中，与 ALS 有关的突变主要位于 C 端的货物结合区，而与遗传性周围神经病变和痉挛性截瘫有关的 KIF1A N 端运动结构域突变则不在此列。我们在 KIF1A 基因错义突变的 ALS 患者中观察到高度的临床异质性。我们的调查显示，KIF1A C端的突变可能会增加 ALS 的发病风险，支持 KIF1A 在 ALS 中的致病作用，并扩大了 KIF1A 相关 ALS 的表型和遗传谱。
{"title":"Genetic link between KIF1A mutations and amyotrophic lateral sclerosis: evidence from whole-exome sequencing","authors":"Wei Zheng, Ji He, Lu Chen, Weiyi Yu, Nan Zhang, Xiaoxuan Liu, D. Fan","doi":"10.3389/fnagi.2024.1421841","DOIUrl":"https://doi.org/10.3389/fnagi.2024.1421841","url":null,"abstract":"Genetics have been shown to have a substantial impact on amyotrophic lateral sclerosis (ALS). The ALS process involves defects in axonal transport and cytoskeletal dynamics. It has been identified that KIF1A, responsible for encoding a kinesin-3 motor protein that carries synaptic vesicles, is considered a genetic predisposing factor for ALS.The analysis of whole-exome sequencing data from 1,068 patients was conducted to examine the genetic link between ALS and KIF1A. For patients with KIF1A gene mutations and a family history, we extended the analysis to their families and reanalyzed them using Sanger sequencing for cosegregation analysis.In our cohort, the KIF1A mutation frequency was 1.31% (14/1,068). Thirteen nonsynonymous variants were detected in 14 ALS patients. Consistent with the connection between KIF1A and ALS, the missense mutation p.A1083T (c.3247G>A) was shown to cosegregate with disease. The mutations related to ALS in our study were primarily located in the cargo-binding region at the C-terminal, as opposed to the mutations of motor domain at the N-terminal of KIF1A which were linked to hereditary peripheral neuropathy and spastic paraplegia. We observed high clinical heterogeneity in ALS patients with missense mutations in the KIF1A gene. KIF5A is a more frequent determinant of ALS in the European population, while KIF1A accounts for a similar proportion of ALS in both the European and Chinese populations.Our investigation revealed that mutations in the C-terminus of KIF1A could increase the risk of ALS, support the pathogenic role of KIF1A in ALS and expand the phenotypic and genetic spectrum of KIF1A-related ALS.","PeriodicalId":503985,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"94 7","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141647179","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Alzheimer's disease (AD) is a leading cause of dementia, characterized by the accumulation of amyloid-beta (Aβ) and hyperphosphorylated tau proteins, leading to neuroinflammation and neuronal damage. The role of the immune system in AD pathogenesis is increasingly recognized, prompting an exploration of the causal relationship between immune cells and AD by using Mendelian randomization (MR) approaches.Utilizing genome-wide association study (GWAS) data from European cohorts, we conducted an MR study to investigate the causal links between immune cell phenotypes and AD. We selected single nucleotide polymorphisms (SNPs) associated with immune cell traits at a genome-wide significance threshold and applied various MR methods, including MR Egger, Weighted median, and inverse variance weighted analysis, to assess the causality between 731 immune phenotypes and AD.Our MR analysis identified 15 immune cell types with significant causal relationships to AD pathogenesis. Notably, the absolute count of CD28−CD4−CD8− T cells and the expression of HLA DR on B cells were linked to a protective effect against AD, while 13 other immune phenotypes were identified as contributing to the risk factors for the disease. The causal effects of AD on immunophenotypic traits are predominantly negative, implying that AD may impair the functionality of immune cells. Validation through independent datasets, such as FinnGen and GCST90027158, confirmed the causal association between six specific immune cells and AD.This comprehensive MR study elucidates the intricate network of causal relationships between diverse immunophenotypic traits and AD, providing novel insights into the immunopathogenesis of AD. The findings suggest potential immunological targets that could be leveraged for early diagnosis, disease monitoring, and therapeutic intervention.
{"title":"The role of Immune cells in Alzheimer's disease: a bidirectional Mendelian randomization study","authors":"Erdong Zhang, Tingting Chen, Yanqin Chen, Chenxiang Long, Ling Tao, Xiangchun Shen, Fengqiu Dai","doi":"10.3389/fnagi.2024.1433691","DOIUrl":"https://doi.org/10.3389/fnagi.2024.1433691","url":null,"abstract":"Alzheimer's disease (AD) is a leading cause of dementia, characterized by the accumulation of amyloid-beta (Aβ) and hyperphosphorylated tau proteins, leading to neuroinflammation and neuronal damage. The role of the immune system in AD pathogenesis is increasingly recognized, prompting an exploration of the causal relationship between immune cells and AD by using Mendelian randomization (MR) approaches.Utilizing genome-wide association study (GWAS) data from European cohorts, we conducted an MR study to investigate the causal links between immune cell phenotypes and AD. We selected single nucleotide polymorphisms (SNPs) associated with immune cell traits at a genome-wide significance threshold and applied various MR methods, including MR Egger, Weighted median, and inverse variance weighted analysis, to assess the causality between 731 immune phenotypes and AD.Our MR analysis identified 15 immune cell types with significant causal relationships to AD pathogenesis. Notably, the absolute count of CD28−CD4−CD8− T cells and the expression of HLA DR on B cells were linked to a protective effect against AD, while 13 other immune phenotypes were identified as contributing to the risk factors for the disease. The causal effects of AD on immunophenotypic traits are predominantly negative, implying that AD may impair the functionality of immune cells. Validation through independent datasets, such as FinnGen and GCST90027158, confirmed the causal association between six specific immune cells and AD.This comprehensive MR study elucidates the intricate network of causal relationships between diverse immunophenotypic traits and AD, providing novel insights into the immunopathogenesis of AD. The findings suggest potential immunological targets that could be leveraged for early diagnosis, disease monitoring, and therapeutic intervention.","PeriodicalId":503985,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"106 6","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141647443","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-15DOI: 10.3389/fnagi.2024.1423139
Wenxian Sun, Jin Gong, Shaoqi Li, Pin Wang, Xiaodong Han, Chang Xu, Heya Luan, Ruina Li, Boye Wen, Cuibai Wei
Alzheimer’s disease (AD) is the predominant cause of dementia on a global scale, significantly impacting the health of the elderly population. The pathogenesis of AD is closely linked to neuroinflammation. The present study employs a bibliometric analysis to examine research pertaining to neuroinflammation and AD within the last decade, with the objective of providing a comprehensive overview of the current research profile, hotspots and trends.This research conducted a comprehensive review of publications within the Science Citation Index Expanded of the Web of Science Core Collection Database spanning the years 2014 to 2024. Bibliometric analyses were performed using VOSviewer (version 1.6.19) and CiteSpace (version 6.3.R1) software to visualize data on countries, institutions, authors, journals, keywords, and references.A total of 3,833 publications on neuroinflammation and AD were included from January 2014 to January 2024. Publications were mainly from the United States and China. Zetterberg, Henrik emerged as the author with the highest publication output, while Edison, Paul was identified as the most cited author. The most productive journal was Journal of Alzheimers Disease, and the most co-cited was Journal of Neuroinflammation. Research hotspot focused on microglia, mouse models, oxidative stress, and amyloid-beta through keyword analysis. Additionally, keywords such as blood–brain barrier and tau protein exhibited prolonged citation bursts from 2022 to 2024.This study provides a comprehensive review of the last 10 years of research on neuroinflammation and AD, including the number and impact of research findings, research hotspots, and future trends. The quantity of publications in this field is increasing, mainly in the United States and China, and there is a need to further strengthen close cooperation with different countries and institutions worldwide. Presently, research hotspots are primarily concentrated on microglia, with a focus on inhibiting their pro-inflammatory responses and promoting their anti-inflammatory functions as a potential direction for future investigations.
阿尔茨海默病（AD）是全球痴呆症的主要病因，严重影响老年人群的健康。阿尔茨海默病的发病机制与神经炎症密切相关。本研究采用文献计量学分析方法，对过去十年间有关神经炎症和AD的研究进行了梳理，旨在全面概述当前的研究概况、热点和趋势。使用VOSviewer（1.6.19版）和CiteSpace（6.3.R1版）软件对文献计量学进行了分析，以可视化国家、机构、作者、期刊、关键词和参考文献的数据。论文主要来自美国和中国。亨里克-泽特伯格（Zetterberg, Henrik）是发表论文最多的作者，而保罗-爱迪生（Edison, Paul）则是被引用次数最多的作者。发表论文最多的期刊是《阿尔茨海默病杂志》（Journal of Alzheimers Disease），被联合引用最多的是《神经炎症杂志》（Journal of Neuroinflammation）。通过关键词分析，研究热点集中在小胶质细胞、小鼠模型、氧化应激和淀粉样蛋白-β。此外，血脑屏障和tau蛋白等关键词在2022年至2024年表现出长时间的引用爆发。本研究全面回顾了过去10年有关神经炎症和AD的研究，包括研究成果的数量和影响、研究热点和未来趋势。该领域的论文数量不断增加，主要集中在美国和中国，需要进一步加强与世界不同国家和机构的密切合作。目前，研究热点主要集中在小胶质细胞，重点是抑制其促炎症反应和促进其抗炎功能，这也是未来研究的潜在方向。
{"title":"Bibliometric analysis of neuroinflammation and Alzheimer’s disease","authors":"Wenxian Sun, Jin Gong, Shaoqi Li, Pin Wang, Xiaodong Han, Chang Xu, Heya Luan, Ruina Li, Boye Wen, Cuibai Wei","doi":"10.3389/fnagi.2024.1423139","DOIUrl":"https://doi.org/10.3389/fnagi.2024.1423139","url":null,"abstract":"Alzheimer’s disease (AD) is the predominant cause of dementia on a global scale, significantly impacting the health of the elderly population. The pathogenesis of AD is closely linked to neuroinflammation. The present study employs a bibliometric analysis to examine research pertaining to neuroinflammation and AD within the last decade, with the objective of providing a comprehensive overview of the current research profile, hotspots and trends.This research conducted a comprehensive review of publications within the Science Citation Index Expanded of the Web of Science Core Collection Database spanning the years 2014 to 2024. Bibliometric analyses were performed using VOSviewer (version 1.6.19) and CiteSpace (version 6.3.R1) software to visualize data on countries, institutions, authors, journals, keywords, and references.A total of 3,833 publications on neuroinflammation and AD were included from January 2014 to January 2024. Publications were mainly from the United States and China. Zetterberg, Henrik emerged as the author with the highest publication output, while Edison, Paul was identified as the most cited author. The most productive journal was Journal of Alzheimers Disease, and the most co-cited was Journal of Neuroinflammation. Research hotspot focused on microglia, mouse models, oxidative stress, and amyloid-beta through keyword analysis. Additionally, keywords such as blood–brain barrier and tau protein exhibited prolonged citation bursts from 2022 to 2024.This study provides a comprehensive review of the last 10 years of research on neuroinflammation and AD, including the number and impact of research findings, research hotspots, and future trends. The quantity of publications in this field is increasing, mainly in the United States and China, and there is a need to further strengthen close cooperation with different countries and institutions worldwide. Presently, research hotspots are primarily concentrated on microglia, with a focus on inhibiting their pro-inflammatory responses and promoting their anti-inflammatory functions as a potential direction for future investigations.","PeriodicalId":503985,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"54 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141648601","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-23DOI: 10.3389/fnagi.2024.1388795
C. Jing, Xiaojiao Zhong, Xuli Min, Hao Xu
Parkinson’s disease (PD) is a chronic neurodegenerative disease that affects the central nervous system, primarily the motor nervous system, and occurs most often in older adults. A large number of studies have shown that high intelligence leads to an increased risk of PD. However, whether there is a causal relationship between intelligence on PD has not yet been reported.In this study, Mendelian randomization (MR) analysis was performed with intelligence (ebi-a-GCST006250) and fluid intelligence score (ukb-b-5238) as exposure factors and PD (ieu-b-7) as an outcome, which the datasets were mined from the IEU OpenGWAS database. MR analysis was performed through 3 methods [MR Egger, weighted median, inverse variance weighted (IVW)], of which IVW was the primary method. In addition, the reliability of the results of the MR analysis was assessed via the heterogeneity test, the horizontal polytropy test, and Leave-One-Out (LOO). Finally, based on gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases, the genes corresponding to intelligence and fluid intelligence score related to SNPs were enriched for functional features and pathways.The results of MR analysis suggested that elevated intelligence indicators can increase the risk of PD [p = 0.015, Odd Ratio (OR) = 1.316]. Meanwhile, fluid intelligence score was causally associated with the PD (p = 0.035), which was a risk factor (OR = 1.142). The reliability of the results of MR analysis was demonstrated by sensitivity analysis. Finally, the results of GO enrichment analysis for 87 genes corresponding to intelligence related SNPs mainly included regulation of synapse organization, developmental cell growth, etc. These genes were enriched in the synaptic vessel cycle, polycomb expressive complex in KEGG. Similarly, 44 genes corresponding to SNPs associated with fluid intelligence score were used for enrichment analysis. Based on the GO database, these genes were mainly enriched in regulation of developmental growth, negative regulation of neuron projection development, etc. In KEGG, 44 genes corresponding to SNPs associated with fluid intelligence score were enriched in signaling pathways including Alzheimer’s disease, the cellular senescence, etc.The causal relationships between intelligence and fluid intelligence scores, and PD were demonstrated through MR analysis, providing an important reference and evidence for the study of PD.
帕金森病（PD）是一种影响中枢神经系统（主要是运动神经系统）的慢性神经退行性疾病，多发于老年人。大量研究表明，高智商会增加帕金森病的患病风险。本研究以智力（ebi-a-GCST006250）和流体智力评分（ukb-b-5238）为暴露因子，以脊髓灰质炎（ieu-b-7）为结局，进行了孟德尔随机化（MR）分析。MR分析通过3种方法[MR Egger、加权中位数、逆方差加权（IVW）]进行，其中IVW是主要方法。此外，还通过异质性检验、水平多向性检验和留空（LOO）评估了 MR 分析结果的可靠性。最后，基于基因本体论（GO）和京都基因与基因组百科全书（KEGG）数据库，对与SNPs相关的智力和流体智力评分对应的基因进行了功能特征和通路富集。同时，流体智力评分与帕金森病有因果关系（p = 0.035），是一种危险因素（OR = 1.142）。敏感性分析表明了 MR 分析结果的可靠性。最后，与智力相关的 SNP 对应的 87 个基因的 GO 富集分析结果主要包括突触组织调控、发育细胞生长等。这些基因在 KEG 中富集于突触血管循环、多聚酶表达复合体。同样，与流体智力评分相关的 SNPs 所对应的 44 个基因也被用于富集分析。根据 GO 数据库，这些基因主要富集在发育生长调控、神经元投射发育负调控等方面。在KEGG中，与流体智力评分相关的SNP对应的44个基因富集在信号通路中，包括阿尔茨海默病、细胞衰老等。通过MR分析，证明了智力和流体智力评分与PD之间的因果关系，为研究PD提供了重要的参考和证据。
{"title":"The causal effects of intelligence and fluid intelligence on Parkinson’s disease: a Mendelian randomization study","authors":"C. Jing, Xiaojiao Zhong, Xuli Min, Hao Xu","doi":"10.3389/fnagi.2024.1388795","DOIUrl":"https://doi.org/10.3389/fnagi.2024.1388795","url":null,"abstract":"Parkinson’s disease (PD) is a chronic neurodegenerative disease that affects the central nervous system, primarily the motor nervous system, and occurs most often in older adults. A large number of studies have shown that high intelligence leads to an increased risk of PD. However, whether there is a causal relationship between intelligence on PD has not yet been reported.In this study, Mendelian randomization (MR) analysis was performed with intelligence (ebi-a-GCST006250) and fluid intelligence score (ukb-b-5238) as exposure factors and PD (ieu-b-7) as an outcome, which the datasets were mined from the IEU OpenGWAS database. MR analysis was performed through 3 methods [MR Egger, weighted median, inverse variance weighted (IVW)], of which IVW was the primary method. In addition, the reliability of the results of the MR analysis was assessed via the heterogeneity test, the horizontal polytropy test, and Leave-One-Out (LOO). Finally, based on gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases, the genes corresponding to intelligence and fluid intelligence score related to SNPs were enriched for functional features and pathways.The results of MR analysis suggested that elevated intelligence indicators can increase the risk of PD [p = 0.015, Odd Ratio (OR) = 1.316]. Meanwhile, fluid intelligence score was causally associated with the PD (p = 0.035), which was a risk factor (OR = 1.142). The reliability of the results of MR analysis was demonstrated by sensitivity analysis. Finally, the results of GO enrichment analysis for 87 genes corresponding to intelligence related SNPs mainly included regulation of synapse organization, developmental cell growth, etc. These genes were enriched in the synaptic vessel cycle, polycomb expressive complex in KEGG. Similarly, 44 genes corresponding to SNPs associated with fluid intelligence score were used for enrichment analysis. Based on the GO database, these genes were mainly enriched in regulation of developmental growth, negative regulation of neuron projection development, etc. In KEGG, 44 genes corresponding to SNPs associated with fluid intelligence score were enriched in signaling pathways including Alzheimer’s disease, the cellular senescence, etc.The causal relationships between intelligence and fluid intelligence scores, and PD were demonstrated through MR analysis, providing an important reference and evidence for the study of PD.","PeriodicalId":503985,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"108 6","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141105837","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-23DOI: 10.3389/fnagi.2024.1389957
Zejun Liu, Yujuan Wang, Yajun Zhu, Jing Yuan, Wei Liu
The finding that familiarity can support associative memory by unitizing the to -be-learned items into a novel representation has been widely accepted, but its effects on overall performance of associative memory and recollection are still controversial.The current study aims to elucidate these discrepancies by identifying potential moderating factors through a combined approach of meta-analysis and behavioral experiment.Results consistently showed that changes in the level of unitization and age groups were two important moderators. Specifically, unitization enhanced younger and older adults’ associative memory and its supporting processes (i.e., familiarity and recollection) when the level of unitization between studied and rearranged pairs was changed. However, when this level remained constant, unitization exhibited no impact on associative memory and familiarity in younger adults, but showed an enhanced effect in older adults. Furthermore, results revealed a marked group difference between younger and older adults in associative memory when the unitization level of noncompound words remained unaltered. Upon breaking this condition, the group difference was reduced by enhancing familiarity or recollection.These findings not only clarify some of the inconsistencies in the literature concerning the impact of unitization on associative memory, but also suggest that unitization is a beneficial strategy for reducing group difference in associative memory, with its effectiveness varying according to the level of unitization changes.
{"title":"Improving associative memory in younger and older adults with unitization: evidence from meta-analysis and behavioral studies","authors":"Zejun Liu, Yujuan Wang, Yajun Zhu, Jing Yuan, Wei Liu","doi":"10.3389/fnagi.2024.1389957","DOIUrl":"https://doi.org/10.3389/fnagi.2024.1389957","url":null,"abstract":"The finding that familiarity can support associative memory by unitizing the to -be-learned items into a novel representation has been widely accepted, but its effects on overall performance of associative memory and recollection are still controversial.The current study aims to elucidate these discrepancies by identifying potential moderating factors through a combined approach of meta-analysis and behavioral experiment.Results consistently showed that changes in the level of unitization and age groups were two important moderators. Specifically, unitization enhanced younger and older adults’ associative memory and its supporting processes (i.e., familiarity and recollection) when the level of unitization between studied and rearranged pairs was changed. However, when this level remained constant, unitization exhibited no impact on associative memory and familiarity in younger adults, but showed an enhanced effect in older adults. Furthermore, results revealed a marked group difference between younger and older adults in associative memory when the unitization level of noncompound words remained unaltered. Upon breaking this condition, the group difference was reduced by enhancing familiarity or recollection.These findings not only clarify some of the inconsistencies in the literature concerning the impact of unitization on associative memory, but also suggest that unitization is a beneficial strategy for reducing group difference in associative memory, with its effectiveness varying according to the level of unitization changes.","PeriodicalId":503985,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"18 14","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141104599","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Soluble triggering receptor expressed on myeloid cells 2 (sTREM2) is a potential neuroinflammatory biomarker linked to the pathogenesis of Alzheimer’s disease (AD) and mild cognitive impairment (MCI). Previous studies have produced inconsistent results regarding sTREM2 levels in various clinical stages of AD. This study aims to establish the correlation between sTREM2 levels and AD progression through a meta-analysis of sTREM2 levels in cerebrospinal fluid (CSF) and blood.Comprehensive searches were conducted in PubMed, Embase, Web of Science, and the Cochrane Library to identify observational studies reporting CSF and blood sTREM2 levels in AD patients, MCI patients, and healthy controls. A random effects meta-analysis was used to calculate the standardized mean difference (SMD) and 95% confidence intervals (CIs).Thirty-six observational studies involving 3,016 AD patients, 3,533 MCI patients, and 4,510 healthy controls were included. CSF sTREM2 levels were significantly higher in both the AD [SMD = 0.28, 95% CI (0.15, 0.41)] and MCI groups [SMD = 0.30, 95% CI (0.13, 0.47)] compared to the healthy control group. However, no significant differences in expression were detected between the AD and MCI groups [SMD = 0.09, 95% CI (−0.09, 0.26)]. Furthermore, increased plasma sTREM2 levels were associated with a higher risk of AD [SMD = 0.42, 95% CI (0.01, 0.83)].CSF sTREM2 levels are positively associated with an increased risk of AD and MCI. Plasma sTREM2 levels were notably higher in the AD group than in the control group and may serve as a promising biomarker for diagnosing AD. However, sTREM2 levels are not effective for distinguishing between different disease stages of AD. Further investigations are needed to explore the longitudinal changes in sTREM2 levels, particularly plasma sTREM2 levels, during AD progression.https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42024514593
髓系细胞上表达的可溶性触发受体 2（sTREM2）是一种潜在的神经炎症生物标志物，与阿尔茨海默病（AD）和轻度认知障碍（MCI）的发病机制有关。以往的研究对不同临床阶段阿尔茨海默病的 sTREM2 水平得出了不一致的结果。本研究旨在通过对脑脊液（CSF）和血液中的sTREM2水平进行荟萃分析，确定sTREM2水平与AD进展之间的相关性。我们在PubMed、Embase、Web of Science和Cochrane图书馆进行了全面检索，以确定报告AD患者、MCI患者和健康对照者CSF和血液中sTREM2水平的观察性研究。该研究纳入了36项观察性研究，涉及3016名AD患者、3533名MCI患者和4510名健康对照者。与健康对照组相比，AD 组[SMD = 0.28，95% CI (0.15，0.41)]和 MCI 组[SMD = 0.30，95% CI (0.13，0.47)]的 CSF sTREM2 水平均显著升高。然而，在AD组和MCI组之间没有发现明显的表达差异[SMD = 0.09, 95% CI (-0.09, 0.26)]。此外，血浆sTREM2水平升高与AD风险升高有关[SMD = 0.42，95% CI (0.01，0.83)]。AD组血浆sTREM2水平明显高于对照组，可作为诊断AD的一种有前途的生物标志物。然而，sTREM2水平并不能有效区分AD的不同疾病阶段。在AD进展过程中，sTREM2水平，尤其是血浆sTREM2水平的纵向变化还需要进一步研究。https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42024514593
{"title":"Association of soluble TREM2 with Alzheimer’s disease and mild cognitive impairment: a systematic review and meta-analysis","authors":"Ruiqi Wang, Yi-jun Zhan, Wen-Qing Zhu, Qianwen Yang, Jian Pei","doi":"10.3389/fnagi.2024.1407980","DOIUrl":"https://doi.org/10.3389/fnagi.2024.1407980","url":null,"abstract":"Soluble triggering receptor expressed on myeloid cells 2 (sTREM2) is a potential neuroinflammatory biomarker linked to the pathogenesis of Alzheimer’s disease (AD) and mild cognitive impairment (MCI). Previous studies have produced inconsistent results regarding sTREM2 levels in various clinical stages of AD. This study aims to establish the correlation between sTREM2 levels and AD progression through a meta-analysis of sTREM2 levels in cerebrospinal fluid (CSF) and blood.Comprehensive searches were conducted in PubMed, Embase, Web of Science, and the Cochrane Library to identify observational studies reporting CSF and blood sTREM2 levels in AD patients, MCI patients, and healthy controls. A random effects meta-analysis was used to calculate the standardized mean difference (SMD) and 95% confidence intervals (CIs).Thirty-six observational studies involving 3,016 AD patients, 3,533 MCI patients, and 4,510 healthy controls were included. CSF sTREM2 levels were significantly higher in both the AD [SMD = 0.28, 95% CI (0.15, 0.41)] and MCI groups [SMD = 0.30, 95% CI (0.13, 0.47)] compared to the healthy control group. However, no significant differences in expression were detected between the AD and MCI groups [SMD = 0.09, 95% CI (−0.09, 0.26)]. Furthermore, increased plasma sTREM2 levels were associated with a higher risk of AD [SMD = 0.42, 95% CI (0.01, 0.83)].CSF sTREM2 levels are positively associated with an increased risk of AD and MCI. Plasma sTREM2 levels were notably higher in the AD group than in the control group and may serve as a promising biomarker for diagnosing AD. However, sTREM2 levels are not effective for distinguishing between different disease stages of AD. Further investigations are needed to explore the longitudinal changes in sTREM2 levels, particularly plasma sTREM2 levels, during AD progression.https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42024514593","PeriodicalId":503985,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"62 40","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141110437","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-22DOI: 10.3389/fnagi.2024.1414956
Xingzhi Yu, Jie Tao, Tian Xiao, Xiaohua Duan
Gastrodia elata is the dried tuber of the orchid Gastrodia elata Bl. It is considered a food consisting of a source of precious medicinal herbs, whose chemical composition is relatively rich. Gastrodia elata and its extracted fractions have been shown to have neuroprotective effects. P-hydroxybenzaldehyde (p-HBA), as one of the main active components of Gastrodia elata, has anti-inflammatory, antioxidative stress, and cerebral protective effects, which has potential for the treatment of Alzheimer’s disease (AD). The aim of this study was to verify the role of p-HBA in AD treatment and to investigate its mechanism of action in depth based using the Caenorhabditis elegans (C. elegans) model.In this study, we used paralysis, lifespan, behavioral and antistress experiments to investigate the effects of p-HBA on AD and aging. Furthermore, we performed reactive oxygen species (ROS) assay, thioflavin S staining, RNA-seq analysis, qPCR validation, PCR Array, and GFP reporter gene worm experiment to determine the anti-AD effects of p-HBA, as well as in-depth studies on its mechanisms.p-HBA was able to delay paralysis, improve mobility and resistance to stress, and delay aging in the AD nematode model. Further mechanistic studies showed that ROS and lipofuscin levels, Aβ aggregation, and toxicity were reduced after p-HBA treatment, suggesting that p-HBA ameliorated Aβ-induced toxicity by enhancing antioxidant and anti-aging activity and inhibiting Aβ aggregation. p-HBA had a therapeutic effect on AD by improving stress resistance, as indicated by the down-regulation of NLP-29 and UCR-11 expression and up-regulation of PQN-75 and LYS-3 expression. In addition, the gene microarray showed that p-HBA treatment played a positive role in genes related to AD, anti-aging, ribosomal protein pathway, and glucose metabolism, which were collectively involved in the anti-AD mechanism of p-HBA. Finally, we also found that p-HBA promoted nuclear localization of DAF-16 and increased the expression of SKN-1, SOD-3, and GST-4, which contributed significantly to inhibition of Aβ toxicity and enhancement of antioxidative stress.Our work suggests that p-HBA has some antioxidant and anti-aging activities. It may be a viable candidate for the treatment and prevention of Alzheimer’s disease.
天麻是兰科植物天麻（Gastrodia elata Bl）的干燥块茎，被认为是一种含有珍贵药材的食品，其化学成分相对丰富。天麻及其提取物具有保护神经的作用。对羟基苯甲醛（p-HBA）是天麻的主要活性成分之一，具有抗炎、抗氧化和保护大脑的作用，有望用于治疗阿尔茨海默病（AD）。本研究的目的是利用秀丽隐杆线虫（C. elegans）模型，验证 p-HBA 在 AD 治疗中的作用，并深入研究其作用机制。此外，我们还进行了活性氧（ROS）检测、硫黄素S染色、RNA-seq分析、qPCR验证、PCR Array和GFP报告基因蠕虫实验，以确定p-HBA的抗AD作用，并对其机制进行了深入研究。进一步的机理研究表明，经p-HBA处理后，ROS和脂褐素水平、Aβ聚集和毒性均有所降低，表明p-HBA通过增强抗氧化和抗衰老活性以及抑制Aβ聚集来改善Aβ诱导的毒性。此外，基因芯片显示，p-HBA 处理对与 AD、抗衰老、核糖体蛋白通路和糖代谢相关的基因有积极作用，这些基因共同参与了 p-HBA 的抗 AD 机制。最后，我们还发现，p-HBA能促进DAF-16的核定位，增加SKN-1、SOD-3和GST-4的表达，这对抑制Aβ毒性和增强抗氧化应激有重要作用。我们的研究表明，p-HBA 具有一定的抗氧化和抗衰老活性，可能是治疗和预防阿尔茨海默病的可行候选药物。
{"title":"P-hydroxybenzaldehyde protects Caenorhabditis elegans from oxidative stress and β-amyloid toxicity","authors":"Xingzhi Yu, Jie Tao, Tian Xiao, Xiaohua Duan","doi":"10.3389/fnagi.2024.1414956","DOIUrl":"https://doi.org/10.3389/fnagi.2024.1414956","url":null,"abstract":"Gastrodia elata is the dried tuber of the orchid Gastrodia elata Bl. It is considered a food consisting of a source of precious medicinal herbs, whose chemical composition is relatively rich. Gastrodia elata and its extracted fractions have been shown to have neuroprotective effects. P-hydroxybenzaldehyde (p-HBA), as one of the main active components of Gastrodia elata, has anti-inflammatory, antioxidative stress, and cerebral protective effects, which has potential for the treatment of Alzheimer’s disease (AD). The aim of this study was to verify the role of p-HBA in AD treatment and to investigate its mechanism of action in depth based using the Caenorhabditis elegans (C. elegans) model.In this study, we used paralysis, lifespan, behavioral and antistress experiments to investigate the effects of p-HBA on AD and aging. Furthermore, we performed reactive oxygen species (ROS) assay, thioflavin S staining, RNA-seq analysis, qPCR validation, PCR Array, and GFP reporter gene worm experiment to determine the anti-AD effects of p-HBA, as well as in-depth studies on its mechanisms.p-HBA was able to delay paralysis, improve mobility and resistance to stress, and delay aging in the AD nematode model. Further mechanistic studies showed that ROS and lipofuscin levels, Aβ aggregation, and toxicity were reduced after p-HBA treatment, suggesting that p-HBA ameliorated Aβ-induced toxicity by enhancing antioxidant and anti-aging activity and inhibiting Aβ aggregation. p-HBA had a therapeutic effect on AD by improving stress resistance, as indicated by the down-regulation of NLP-29 and UCR-11 expression and up-regulation of PQN-75 and LYS-3 expression. In addition, the gene microarray showed that p-HBA treatment played a positive role in genes related to AD, anti-aging, ribosomal protein pathway, and glucose metabolism, which were collectively involved in the anti-AD mechanism of p-HBA. Finally, we also found that p-HBA promoted nuclear localization of DAF-16 and increased the expression of SKN-1, SOD-3, and GST-4, which contributed significantly to inhibition of Aβ toxicity and enhancement of antioxidative stress.Our work suggests that p-HBA has some antioxidant and anti-aging activities. It may be a viable candidate for the treatment and prevention of Alzheimer’s disease.","PeriodicalId":503985,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"62 17","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141110553","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-22DOI: 10.3389/fnagi.2024.1395553
Xin Zhang, Zhen Wang, Jing Zou, Le Zhang, Jinghua Ning, Bei Jiang, Yi Liang, Yuzhe Zhang
Physical weakness is associated with cortical structures, but the exact causes remain to be investigated. Therefore, we utilized Mendelian randomization (MR) analysis to uncover the underlying connection between frailty and cortical structures.The Genome-Wide Association Study (GWAS) on frailty pooled data from publicly available sources such as the UK Biobank and included five indicators of frailty: weakness, walking speed, weight loss, physical activity, and exhaustion. GWAS data on cerebral cortical structure were obtained from the ENIGMA consortium, and we assessed the causal relationship between hereditary frailty and cortical surface area (SA) or cortical thickness (TH). Inverse variance weighting (IVW) was used as the primary estimate, and heterogeneity and multidimensionality were monitored by MR-PRESSO to detect outliers. Additionally, MR-Egger, Cochran’s Q test, and weighted median were employed.At the aggregate level, there was no causal relationship between frailty and cortical thickness or surface area. At the regional level, frailty was associated with the thickness of the middle temporal lobe, parahippocampus, rostral middle frontal lobe, lower parietal lobe, anterior cingulate gyrus, upper temporal lobe, lateral orbital frontal cortex, pericardial surface area, rostral middle frontal lobe, upper temporal lobe, rostral anterior cingulate gyrus, lower parietal lobe, and upper parietal lobe. These results were nominally significant, and sensitivity analyses did not detect any multidirectionality or heterogeneity, suggesting that the results of our analyses are reliable.The results of our analyses suggest a potential causal relationship between somatic weakness and multiple regions of cortical structure. However, the specific mechanisms of influence remain to be investigated. Preliminary results from our analysis suggest that the effects of physical frailty on cortical structures are influenced by various factors related to frailty exposure. This relationship has been documented, and it is therefore both feasible and meaningful to build on existing research to explore the clinical significance of the relationship.
{"title":"Association between physical frailty and cortical structure in middle-aged and elderly people: a Mendelian randomization study","authors":"Xin Zhang, Zhen Wang, Jing Zou, Le Zhang, Jinghua Ning, Bei Jiang, Yi Liang, Yuzhe Zhang","doi":"10.3389/fnagi.2024.1395553","DOIUrl":"https://doi.org/10.3389/fnagi.2024.1395553","url":null,"abstract":"Physical weakness is associated with cortical structures, but the exact causes remain to be investigated. Therefore, we utilized Mendelian randomization (MR) analysis to uncover the underlying connection between frailty and cortical structures.The Genome-Wide Association Study (GWAS) on frailty pooled data from publicly available sources such as the UK Biobank and included five indicators of frailty: weakness, walking speed, weight loss, physical activity, and exhaustion. GWAS data on cerebral cortical structure were obtained from the ENIGMA consortium, and we assessed the causal relationship between hereditary frailty and cortical surface area (SA) or cortical thickness (TH). Inverse variance weighting (IVW) was used as the primary estimate, and heterogeneity and multidimensionality were monitored by MR-PRESSO to detect outliers. Additionally, MR-Egger, Cochran’s Q test, and weighted median were employed.At the aggregate level, there was no causal relationship between frailty and cortical thickness or surface area. At the regional level, frailty was associated with the thickness of the middle temporal lobe, parahippocampus, rostral middle frontal lobe, lower parietal lobe, anterior cingulate gyrus, upper temporal lobe, lateral orbital frontal cortex, pericardial surface area, rostral middle frontal lobe, upper temporal lobe, rostral anterior cingulate gyrus, lower parietal lobe, and upper parietal lobe. These results were nominally significant, and sensitivity analyses did not detect any multidirectionality or heterogeneity, suggesting that the results of our analyses are reliable.The results of our analyses suggest a potential causal relationship between somatic weakness and multiple regions of cortical structure. However, the specific mechanisms of influence remain to be investigated. Preliminary results from our analysis suggest that the effects of physical frailty on cortical structures are influenced by various factors related to frailty exposure. This relationship has been documented, and it is therefore both feasible and meaningful to build on existing research to explore the clinical significance of the relationship.","PeriodicalId":503985,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"46 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141108947","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-21DOI: 10.3389/fnagi.2024.1393351
Azhaar Ashraf, Manal Aljuhani, Chantal J. Hubens, Jérôme Jeandriens, Harold G. Parkes, K. Geraki, A. Mahmood, Amy H. Herlihy, Po-Wah So
Iron dyshomeostasis and neuroinflammation, characteristic features of the aged brain, and exacerbated in neurodegenerative disease, may induce oxidative stress-mediated neurodegeneration. In this study, the effects of potential priming with mild systemic iron injections on subsequent lipopolysaccharide (LPS)-induced inflammation in adult C57Bl/6J mice were examined. After cognitive testing, regional brain tissues were dissected for iron (metal) measurements by total reflection X-ray fluorescence and synchrotron radiation X-Ray fluorescence-based elemental mapping; and iron regulatory, ferroptosis-related, and glia-specific protein analysis, and lipid peroxidation by western blotting. Microglial morphology and astrogliosis were assessed by immunohistochemistry. Iron only treatment enhanced cognitive performance on the novel object location task compared with iron priming and subsequent LPS-induced inflammation. LPS-induced inflammation, with or without iron treatment, attenuated hippocampal heme oxygenase-1 and augmented 4-hydroxynonenal levels. Conversely, in the cortex, elevated ferritin light chain and xCT (light chain of System Xc−) were observed in response to LPS-induced inflammation, without and with iron-priming. Increased microglial branch/process lengths and astrocyte immunoreactivity were also increased by combined iron and LPS in both the hippocampus and cortex. Here, we demonstrate iron priming and subsequent LPS-induced inflammation led to iron dyshomeostasis, compromised antioxidant function, increased lipid peroxidation and altered neuroinflammatory state in a brain region-dependent manner.
铁失衡和神经炎症是老年大脑的特征，在神经退行性疾病中会加剧，可能诱发氧化应激介导的神经退行性病变。在这项研究中，研究人员研究了轻度全身性铁注射对成年 C57Bl/6J 小鼠随后由脂多糖（LPS）诱发的炎症的潜在影响。认知测试结束后，解剖区域脑组织，通过全反射 X 射线荧光和同步辐射 X 射线荧光元素图谱测量铁（金属）含量，并通过 Western 印迹分析铁调节蛋白、铁突变相关蛋白、胶质细胞特异性蛋白和脂质过氧化物。免疫组化法评估了小胶质细胞形态和星形胶质细胞增多情况。与铁引物和随后的LPS诱导炎症相比，只用铁治疗能提高新物体定位任务的认知能力。无论是否进行铁治疗，LPS诱导的炎症都会降低海马血红素加氧酶-1的水平，并增加4-羟基壬烯醛的水平。相反，在大脑皮层，铁蛋白轻链和xCT（Xc-系统轻链）的升高是对LPS诱导的炎症的反应，无论是否进行了铁刺激。在海马和皮层中，铁和 LPS 的联合作用也会增加小胶质细胞分支/过程长度和星形胶质细胞免疫活性。在此，我们证明了铁引物和随后的 LPS 诱导的炎症会导致铁失衡、抗氧化功能受损、脂质过氧化增加以及神经炎症状态改变，而这些都是大脑区域依赖性的。
{"title":"Inflammation subsequent to mild iron excess differentially alters regional brain iron metabolism, oxidation and neuroinflammation status in mice","authors":"Azhaar Ashraf, Manal Aljuhani, Chantal J. Hubens, Jérôme Jeandriens, Harold G. Parkes, K. Geraki, A. Mahmood, Amy H. Herlihy, Po-Wah So","doi":"10.3389/fnagi.2024.1393351","DOIUrl":"https://doi.org/10.3389/fnagi.2024.1393351","url":null,"abstract":"Iron dyshomeostasis and neuroinflammation, characteristic features of the aged brain, and exacerbated in neurodegenerative disease, may induce oxidative stress-mediated neurodegeneration. In this study, the effects of potential priming with mild systemic iron injections on subsequent lipopolysaccharide (LPS)-induced inflammation in adult C57Bl/6J mice were examined. After cognitive testing, regional brain tissues were dissected for iron (metal) measurements by total reflection X-ray fluorescence and synchrotron radiation X-Ray fluorescence-based elemental mapping; and iron regulatory, ferroptosis-related, and glia-specific protein analysis, and lipid peroxidation by western blotting. Microglial morphology and astrogliosis were assessed by immunohistochemistry. Iron only treatment enhanced cognitive performance on the novel object location task compared with iron priming and subsequent LPS-induced inflammation. LPS-induced inflammation, with or without iron treatment, attenuated hippocampal heme oxygenase-1 and augmented 4-hydroxynonenal levels. Conversely, in the cortex, elevated ferritin light chain and xCT (light chain of System Xc−) were observed in response to LPS-induced inflammation, without and with iron-priming. Increased microglial branch/process lengths and astrocyte immunoreactivity were also increased by combined iron and LPS in both the hippocampus and cortex. Here, we demonstrate iron priming and subsequent LPS-induced inflammation led to iron dyshomeostasis, compromised antioxidant function, increased lipid peroxidation and altered neuroinflammatory state in a brain region-dependent manner.","PeriodicalId":503985,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"113 6","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141116066","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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