Marlene Zubillaga, Julia Tau, Diana Rosa, M José Bellini, Nathalie Arnal
{"title":"亚致死铜浓度对星形胶质细胞中胆固醇合成的性别依赖性影响及其与神经元膜中胆固醇和淀粉样前体蛋白水平变化的可能联系","authors":"Marlene Zubillaga, Julia Tau, Diana Rosa, M José Bellini, Nathalie Arnal","doi":"10.1186/s13293-023-00578-9","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Cholesterol (Cho) is an essential lipophilic molecule in cells; however, both its decrease and its increase may favor the development of neurological diseases such as Alzheimer's disease (AD). Although copper (Cu) is an essential trace metal for cells, the increased plasma concentration of its free form has been linked with AD development and severity. AD affects aged people, but its prevalence and severity are higher in women than in men. We have previously shown that Cu promotes Cho de novo synthesis in immature neurons as well as increased Cho in membrane rafts and Aβ levels in culture medium, but there are no results yet regarding sex differences in the effects of sublethal Cu exposure on Cho de novo synthesis.</p><p><strong>Methods: </strong>We examined the potential sex-specific impact of sublethal Cu concentrations on de novo Cho synthesis in primary cultures of male and female astrocytes. We also explored whether this had any correlation with variations in Cho and APP levels within neuronal membrane rafts.</p><p><strong>Results: </strong>Flow cytometry analysis demonstrated that Cu treatment leads to a greater increase in ROS levels in female astrocytes than in males. Furthermore, through RT-PCR analysis, we observed an upregulation of SREBP-2 and HMGCR. Consistently, we observed an increase in de novo Cho synthesis. Finally, western blot analysis indicated that the levels of ABCA1 increase after Cu treatment, accompanied by a higher release of radiolabeled Cho and an elevation in Cho and APP levels in neuronal membrane rafts. Importantly, all these results were significantly more pronounced in female astrocytes than in males.</p><p><strong>Conclusions: </strong>Our findings confirm that Cu stimulates Cho synthesis in astrocytes, both in a ROS-dependent and -independent manner. Moreover, female astrocytes displayed elevated levels of HMGCR, and de novo Cho synthesis compared to males following TBH and Cu treatments. This corresponds with higher levels of Cho released into the culture medium and a more significant Cho and APP rise within neuronal rafts. We consider that the increased risk of AD in females partly arises from sex-specific responses to metals and/or exogenous substances, impacting key enzyme regulation in various biochemical pathways, including HMGCR.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":null,"pages":null},"PeriodicalIF":4.9000,"publicationDate":"2024-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10775608/pdf/","citationCount":"0","resultStr":"{\"title\":\"Sex-dependent effect of sublethal copper concentrations on de novo cholesterol synthesis in astrocytes and their possible links to variations in cholesterol and amyloid precursor protein levels in neuronal membranes.\",\"authors\":\"Marlene Zubillaga, Julia Tau, Diana Rosa, M José Bellini, Nathalie Arnal\",\"doi\":\"10.1186/s13293-023-00578-9\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Cholesterol (Cho) is an essential lipophilic molecule in cells; however, both its decrease and its increase may favor the development of neurological diseases such as Alzheimer's disease (AD). Although copper (Cu) is an essential trace metal for cells, the increased plasma concentration of its free form has been linked with AD development and severity. AD affects aged people, but its prevalence and severity are higher in women than in men. We have previously shown that Cu promotes Cho de novo synthesis in immature neurons as well as increased Cho in membrane rafts and Aβ levels in culture medium, but there are no results yet regarding sex differences in the effects of sublethal Cu exposure on Cho de novo synthesis.</p><p><strong>Methods: </strong>We examined the potential sex-specific impact of sublethal Cu concentrations on de novo Cho synthesis in primary cultures of male and female astrocytes. We also explored whether this had any correlation with variations in Cho and APP levels within neuronal membrane rafts.</p><p><strong>Results: </strong>Flow cytometry analysis demonstrated that Cu treatment leads to a greater increase in ROS levels in female astrocytes than in males. Furthermore, through RT-PCR analysis, we observed an upregulation of SREBP-2 and HMGCR. Consistently, we observed an increase in de novo Cho synthesis. Finally, western blot analysis indicated that the levels of ABCA1 increase after Cu treatment, accompanied by a higher release of radiolabeled Cho and an elevation in Cho and APP levels in neuronal membrane rafts. Importantly, all these results were significantly more pronounced in female astrocytes than in males.</p><p><strong>Conclusions: </strong>Our findings confirm that Cu stimulates Cho synthesis in astrocytes, both in a ROS-dependent and -independent manner. Moreover, female astrocytes displayed elevated levels of HMGCR, and de novo Cho synthesis compared to males following TBH and Cu treatments. This corresponds with higher levels of Cho released into the culture medium and a more significant Cho and APP rise within neuronal rafts. We consider that the increased risk of AD in females partly arises from sex-specific responses to metals and/or exogenous substances, impacting key enzyme regulation in various biochemical pathways, including HMGCR.</p>\",\"PeriodicalId\":8890,\"journal\":{\"name\":\"Biology of Sex Differences\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":4.9000,\"publicationDate\":\"2024-01-08\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10775608/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Biology of Sex Differences\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1186/s13293-023-00578-9\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"ENDOCRINOLOGY & METABOLISM\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Biology of Sex Differences","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1186/s13293-023-00578-9","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ENDOCRINOLOGY & METABOLISM","Score":null,"Total":0}
引用次数: 0
摘要
背景:胆固醇(Cholesterol,Cho)是细胞中不可或缺的亲脂分子;然而,胆固醇的减少和增加都可能有利于阿尔茨海默病(Alzheimer's disease,AD)等神经系统疾病的发展。虽然铜(Cu)是细胞不可或缺的微量金属,但其游离形式的血浆浓度增加与阿尔茨海默病的发展和严重程度有关。老年痴呆症影响着老年人,但女性的发病率和严重程度均高于男性。我们曾研究发现,Cu能促进未成熟神经元中Cho的从头合成以及膜筏中Cho的增加和培养基中Aβ水平的提高,但关于亚致死性Cu暴露对Cho从头合成影响的性别差异还没有结果:我们研究了亚致死性 Cu 浓度对男性和女性星形胶质细胞原代培养液中 Cho 从头合成的潜在性别特异性影响。我们还探讨了这是否与神经元膜筏中 Cho 和 APP 水平的变化有关:流式细胞术分析表明,Cu 处理导致雌性星形胶质细胞的 ROS 水平比雄性更高。此外,通过 RT-PCR 分析,我们观察到 SREBP-2 和 HMGCR 的上调。同样,我们也观察到 Cho 的合成增加。最后,Western 印迹分析表明,铜处理后 ABCA1 的水平升高,同时放射性标记的 Cho 释放量增加,神经元膜筏中 Cho 和 APP 的水平升高。重要的是,所有这些结果在雌性星形胶质细胞中明显比在雄性星形胶质细胞中更明显:我们的研究结果证实,Cu 能以 ROS 依赖性和非依赖性方式刺激星形胶质细胞中 Cho 的合成。此外,与男性相比,女性星形胶质细胞在接受 TBH 和 Cu 处理后,其 HMGCR 水平和新 Cho 合成水平均有所提高。这与更高水平的 Cho 释放到培养基中以及神经元筏内更显著的 Cho 和 APP 上升相吻合。我们认为,女性罹患注意力缺失症的风险增加,部分原因是女性对金属和/或外源物质的特异性反应影响了各种生化途径中的关键酶调控,包括HMGCR。
Sex-dependent effect of sublethal copper concentrations on de novo cholesterol synthesis in astrocytes and their possible links to variations in cholesterol and amyloid precursor protein levels in neuronal membranes.
Background: Cholesterol (Cho) is an essential lipophilic molecule in cells; however, both its decrease and its increase may favor the development of neurological diseases such as Alzheimer's disease (AD). Although copper (Cu) is an essential trace metal for cells, the increased plasma concentration of its free form has been linked with AD development and severity. AD affects aged people, but its prevalence and severity are higher in women than in men. We have previously shown that Cu promotes Cho de novo synthesis in immature neurons as well as increased Cho in membrane rafts and Aβ levels in culture medium, but there are no results yet regarding sex differences in the effects of sublethal Cu exposure on Cho de novo synthesis.
Methods: We examined the potential sex-specific impact of sublethal Cu concentrations on de novo Cho synthesis in primary cultures of male and female astrocytes. We also explored whether this had any correlation with variations in Cho and APP levels within neuronal membrane rafts.
Results: Flow cytometry analysis demonstrated that Cu treatment leads to a greater increase in ROS levels in female astrocytes than in males. Furthermore, through RT-PCR analysis, we observed an upregulation of SREBP-2 and HMGCR. Consistently, we observed an increase in de novo Cho synthesis. Finally, western blot analysis indicated that the levels of ABCA1 increase after Cu treatment, accompanied by a higher release of radiolabeled Cho and an elevation in Cho and APP levels in neuronal membrane rafts. Importantly, all these results were significantly more pronounced in female astrocytes than in males.
Conclusions: Our findings confirm that Cu stimulates Cho synthesis in astrocytes, both in a ROS-dependent and -independent manner. Moreover, female astrocytes displayed elevated levels of HMGCR, and de novo Cho synthesis compared to males following TBH and Cu treatments. This corresponds with higher levels of Cho released into the culture medium and a more significant Cho and APP rise within neuronal rafts. We consider that the increased risk of AD in females partly arises from sex-specific responses to metals and/or exogenous substances, impacting key enzyme regulation in various biochemical pathways, including HMGCR.
期刊介绍:
Biology of Sex Differences is a unique scientific journal focusing on sex differences in physiology, behavior, and disease from molecular to phenotypic levels, incorporating both basic and clinical research. The journal aims to enhance understanding of basic principles and facilitate the development of therapeutic and diagnostic tools specific to sex differences. As an open-access journal, it is the official publication of the Organization for the Study of Sex Differences and co-published by the Society for Women's Health Research.
Topical areas include, but are not limited to sex differences in: genomics; the microbiome; epigenetics; molecular and cell biology; tissue biology; physiology; interaction of tissue systems, in any system including adipose, behavioral, cardiovascular, immune, muscular, neural, renal, and skeletal; clinical studies bearing on sex differences in disease or response to therapy.