Cell type and sex specific mitochondrial phenotypes in iPSC derived models of Alzheimer's disease.
Cell type and sex specific mitochondrial phenotypes in iPSC derived models of Alzheimer's disease.
复制标题
阿尔茨海默病iPSC衍生模型中的细胞类型和性别特异性线粒体表型。
DOI：
10.3389/fnmol.2023.1201015
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发表时间：
2023
影响因子：
4.8
通讯作者：
Wilkins, Heather M.
中科院分区：
文献类型：
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作者：
Flannagan, Kaitlin;Stopperan, Julia A.;Hauger, Brittany M.;Troutwine, Benjamin R.;Lysaker, Colton R.;Strope, Taylor A.;Csikos Drummond, Vivien;Gilmore, Caleb A.;Swerdlow, Natalie A.;Draper, Julia M.;Gouvion, Cynthia M.;Vivian, Jay L.;Haeri, Mohammad;Swerdlow, Russell H.;Wilkins, Heather M.
在阿尔茨海默病（AD）中观察到线粒体功能障碍。在人类受试者和AD动物模型中观察到线粒体呼吸、细胞色素氧化酶（考克斯）Vmax和线粒体自噬的改变。从诱导多能干细胞（iPSC）衍生的模型可能不会重演这些表型后，从分化的成体细胞重编程。我们检查了iPSC衍生模型中的线粒体功能，包括脑类器官、前脑神经元和星形胶质细胞。从来自堪萨斯大学阿尔茨海默病研究中心（KU ADRC）群组或购自WiCell的成纤维细胞重编程iPSC。总共检查了四个非痴呆和四个散发性AD iPSC系。使用Seahorse XF技术、分光光度法细胞色素氧化酶（考克斯）Vmax测定、荧光测定对模型进行线粒体呼吸分析，以确定线粒体质量、线粒体膜电位、钙、线粒体动力学和线粒体自噬水平。还测量了AD病理学标志。iPSC衍生的神经元和脑类器官在AD受试者中显示降低的考克斯Vmax，在女性组群中具有更严重的缺陷。在星形胶质细胞中未观察到这些结果。来自AD受试者的iPSC衍生的神经元和星形胶质细胞具有降低的线粒体呼吸参数和增加的糖酵解通量。来自AD受试者的iPSC衍生的神经元和星形胶质细胞显示对线粒体膜电位、线粒体超氧化物产生和线粒体钙的性别依赖性影响。来自AD受试者的iPSC神经元在溶酶体中的线粒体定位减少，对线粒体质量具有性别依赖性影响，而来自女性AD受试者的iPSC星形胶质细胞在溶酶体中的线粒体定位增加。来自AD受试者的iPSC衍生的神经元和星形胶质细胞均显示改变的线粒体动力学。iPSC衍生的神经元具有增加的分泌Aβ和对总APP蛋白表达的性别依赖性效应。iPSC衍生的星形胶质细胞在AD衍生的细胞中显示GFAP表达的性别依赖性变化。总体而言，来自AD受试者的iPSC衍生模型以细胞类型和性别依赖性方式显示线粒体表型和AD病理学标志。这些结果突出了性别作为细胞培养研究中生物学变量的重要性。
Mitochondrial dysfunction is observed in Alzheimer’s disease (AD). Altered mitochondrial respiration, cytochrome oxidase (COX) Vmax, and mitophagy are observed in human subjects and animal models of AD. Models derived from induced pluripotent stem cells (iPSCs) may not recapitulate these phenotypes after reprogramming from differentiated adult cells. We examined mitochondrial function across iPSC derived models including cerebral organoids, forebrain neurons, and astrocytes. iPSCs were reprogrammed from fibroblasts either from the University of Kansas Alzheimer’s Disease Research Center (KU ADRC) cohort or purchased from WiCell. A total of four non-demented and four sporadic AD iPSC lines were examined. Models were subjected to mitochondrial respiration analysis using Seahorse XF technology, spectrophotometric cytochrome oxidase (COX) Vmax assays, fluorescent assays to determine mitochondrial mass, mitochondrial membrane potential, calcium, mitochondrial dynamics, and mitophagy levels. AD pathological hallmarks were also measured. iPSC derived neurons and cerebral organoids showed reduced COX Vmax in AD subjects with more profound defects in the female cohort. These results were not observed in astrocytes. iPSC derived neurons and astrocytes from AD subjects had reduced mitochondrial respiration parameters with increased glycolytic flux. iPSC derived neurons and astrocytes from AD subjects showed sex dependent effects on mitochondrial membrane potential, mitochondrial superoxide production, and mitochondrial calcium. iPSC derived neurons from AD subjects had reduced mitochondrial localization in lysosomes with sex dependent effects on mitochondrial mass, while iPSC derived astrocytes from female AD subjects had increased mitochondrial localization to lysosomes. Both iPSC derived neurons and astrocytes from AD subjects showed altered mitochondrial dynamics. iPSC derived neurons had increased secreted Aβ, and sex dependent effects on total APP protein expression. iPSC derived astrocytes showed sex dependent changes in GFAP expression in AD derived cells. Overall, iPSC derived models from AD subjects show mitochondrial phenotypes and AD pathological hallmarks in a cell type and sex dependent manner. These results highlight the importance of sex as a biological variable in cell culture studies.
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影响因子：
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作者：
Ma X;Ding WX
通讯作者：
Ding WX
影响因子：
64.8
作者：
Israel, Mason A.;Yuan, Shauna H.;Bardy, Cedric;Reyna, Sol M.;Mu, Yangling;Herrera, Cheryl;Hefferan, Michael P.;Van Gorp, Sebastiaan;Nazor, Kristopher L.;Boscolo, Francesca S.;Carson, Christian T.;Laurent, Louise C.;Marsala, Martin;Gage, Fred H.;Remes, Anne M.;Koo, Edward H.;Goldstein, Lawrence S. B.
通讯作者：
Goldstein, Lawrence S. B.
DOI：
10.1002/alz.12198
发表时间：
2020-10-08
期刊：
Alzheimer's & dementia : the journal of the Alzheimer's Association
影响因子：
--
作者：
Hou X;Watzlawik JO;Cook C;Liu CC;Kang SS;Lin WL;DeTure M;Heckman MG;Diehl NN;Al-Shaikh FSH;Walton RL;Ross OA;Melrose HL;Ertekin-Taner N;Bu G;Petrucelli L;Fryer JD;Murray ME;Dickson DW;Fiesel FC;Springer W
通讯作者：
Springer W
影响因子：
9.3
作者：
通讯作者：
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影响因子：
8.5
作者：
通讯作者：
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