Amyloid-β Pathology-Specific Cytokine Secretion Suppresses Neuronal Mitochondrial Metabolism.

IF 2.3 4区医学 Q3 BIOPHYSICS Cellular and molecular bioengineering Pub Date : 2023-09-11 eCollection Date: 2023-08-01 DOI:10.1007/s12195-023-00782-y

Madison K Kuhn, Rebecca M Fleeman, Lynne M Beidler, Amanda M Snyder, Dennis C Chan, Elizabeth A Proctor

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Abstract

Introduction: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Supplementary information: The online version contains supplementary material available at 10.1007/s12195-023-00782-y.

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淀粉样蛋白-β病理学特异性细胞因子分泌抑制神经元线粒体代谢。

引言：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。蛋白质沉积引起的胶质细胞激活导致细胞因子分泌和大脑代谢的变化，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尚不清楚。方法：我们使用Luminex XMAP技术在疾病发展的里程碑时间点量化5xFAD AD小鼠模型中的海马细胞因子浓度。与野生型同窝出生的健康衰老相比，我们使用偏最小二乘回归来构建预测疾病进展的细胞因子特征。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，并使用NanoString nCounter系统测量基因表达的下游变化，使用海马细胞外通量活细胞分析仪测量线粒体功能。结果：我们确定了上调的IFNγ、IP-10/CXCL10和IL-9可预测晚期疾病。当健康神经元以患病大脑中发现的比例暴露于这些细胞因子时，包括ATP合酶在内的线粒体电子传递链复合物的基因表达受到抑制。在活细胞中，细胞因子刺激后，线粒体基本和最大呼吸受损。结论：我们在5xFAD AD小鼠模型中确定了一种细胞因子分泌模式，该模式可预测进展中的淀粉样蛋白-β病理，降低线粒体电子运输复合物的表达，并损害健康神经元的线粒体呼吸。我们在疾病特异性免疫线索和受损的神经元代谢之间建立了机制联系，这可能会导致AD中的神经元脆弱性和变性易感性。补充信息：在线版本包含补充材料，可访问10.1007/s12195-023-00782-y。

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来源期刊

Cellular and molecular bioengineering 生物-生物物理

CiteScore

5.60

自引率

3.60%

发文量

审稿时长

>12 weeks

期刊介绍： The field of cellular and molecular bioengineering seeks to understand, so that we may ultimately control, the mechanical, chemical, and electrical processes of the cell. A key challenge in improving human health is to understand how cellular behavior arises from molecular-level interactions. CMBE, an official journal of the Biomedical Engineering Society, publishes original research and review papers in the following seven general areas: Molecular: DNA-protein/RNA-protein interactions, protein folding and function, protein-protein and receptor-ligand interactions, lipids, polysaccharides, molecular motors, and the biophysics of macromolecules that function as therapeutics or engineered matrices, for example. Cellular: Studies of how cells sense physicochemical events surrounding and within cells, and how cells transduce these events into biological responses. Specific cell processes of interest include cell growth, differentiation, migration, signal transduction, protein secretion and transport, gene expression and regulation, and cell-matrix interactions. Mechanobiology: The mechanical properties of cells and biomolecules, cellular/molecular force generation and adhesion, the response of cells to their mechanical microenvironment, and mechanotransduction in response to various physical forces such as fluid shear stress. Nanomedicine: The engineering of nanoparticles for advanced drug delivery and molecular imaging applications, with particular focus on the interaction of such particles with living cells. Also, the application of nanostructured materials to control the behavior of cells and biomolecules.