Amyloid-β Pathology-Specific Cytokine Secretion Suppresses Neuronal Mitochondrial Metabolism.
Amyloid-β Pathology-Specific Cytokine Secretion Suppresses Neuronal Mitochondrial Metabolism.
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DOI：
10.1007/s12195-023-00782-y
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发表时间：
2023-08
影响因子：
2.8
通讯作者：
Proctor, Elizabeth A.
中科院分区：
文献类型：
--
作者：
Kuhn, Madison K.;Fleeman, Rebecca M.;Beidler, Lynne M.;Snyder, Amanda M.;Chan, Dennis C.;Proctor, Elizabeth A.
神经炎症和代谢功能障碍是阿尔茨海默病（AD）大脑的早期改变，被认为有助于疾病的发作和进展。由于蛋白质沉积导致的胶质细胞活化导致细胞因子分泌和脑代谢的变化，这在AD患者中已经观察到。然而，这种免疫代谢反馈回路损伤神经元并导致神经退行性变的机制仍不清楚。我们使用Luminex XMAP技术在疾病发展的里程碑时间点定量AD的5xFAD小鼠模型中的海马细胞因子浓度。我们使用偏最小二乘回归来建立预测疾病进展的细胞因子特征，与野生型同窝仔中的健康衰老相比。我们将疾病定义的细胞因子特征应用于野生型原代神经元培养物，并使用NanoString nCounter系统测量基因表达的下游变化，并使用Seahorse Extracellular Flux活细胞分析仪测量线粒体功能。我们确定了IFNγ、IP-10/CXCL 10和IL-9上调的模式作为晚期疾病的预测。当健康的神经元暴露于患病大脑中发现的比例的这些细胞因子时，线粒体电子传递链复合物（包括ATP合酶）的基因表达受到抑制。在活细胞中，细胞因子刺激后，基础和最大线粒体呼吸受损。我们确定了一种细胞因子分泌模式，可预测5xFAD小鼠AD模型中淀粉样蛋白-β病理的进展，该模型可降低健康神经元中线粒体电子传递复合物的表达并损害线粒体呼吸。我们建立了疾病特异性免疫线索和受损的神经元代谢之间的机制联系，可能导致AD中神经元的脆弱性和易变性。在线版本包含补充材料，可通过10.1007/s12195-023-00782-y获得。
Neuroinflammation and metabolic dysfunction are early alterations in Alzheimer’s disease (AD) brain that are thought to contribute to disease onset and progression. Glial activation due to protein deposition results in cytokine secretion and shifts in brain metabolism, which have been observed in AD patients. However, the mechanism by which this immunometabolic feedback loop can injure neurons and cause neurodegeneration remains unclear. We used Luminex XMAP technology to quantify hippocampal cytokine concentrations in the 5xFAD mouse model of AD at milestone timepoints in disease development. We used partial least squares regression to build cytokine signatures predictive of disease progression, as compared to healthy aging in wild-type littermates. We applied the disease-defining cytokine signature to wild-type primary neuron cultures and measured downstream changes in gene expression using the NanoString nCounter system and mitochondrial function using the Seahorse Extracellular Flux live-cell analyzer. We identified a pattern of up-regulated IFNγ, IP-10/CXCL10, and IL-9 as predictive of advanced disease. When healthy neurons were exposed to these cytokines in proportions found in diseased brain, gene expression of mitochondrial electron transport chain complexes, including ATP synthase, was suppressed. In live cells, basal and maximal mitochondrial respiration were impaired following cytokine stimulation. We identify a pattern of cytokine secretion predictive of progressing amyloid-β pathology in the 5xFAD mouse model of AD that reduces expression of mitochondrial electron transport complexes and impairs mitochondrial respiration in healthy neurons. We establish a mechanistic link between disease-specific immune cues and impaired neuronal metabolism, potentially causing neuronal vulnerability and susceptibility to degeneration in AD. The online version contains supplementary material available at 10.1007/s12195-023-00782-y.
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影响因子：
168.9
作者：
Cagnin, A;Brooks, DJ;Banati, RB
通讯作者：
Banati, RB
影响因子：
3.3
作者：
Biber, K;Dijkstra, I;Boddeke, HWGM
通讯作者：
Boddeke, HWGM
影响因子：
6
作者：
Alves, Michele J.;Goksel, Mustafa;Czeisler, Catherine M.
通讯作者：
Czeisler, Catherine M.
影响因子：
4.8
作者：
De Felice FG;Lourenco MV
通讯作者：
Lourenco MV
DOI：
10.4049/jimmunol.0903382
发表时间：
2010-05-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Chakrabarty P;Ceballos-Diaz C;Beccard A;Janus C;Dickson D;Golde TE;Das P
通讯作者：
Das P