Myeloid cells, aging and the metabolic syndrome

描述（由申请人提供）：炎症有助于代谢综合征，包括胰岛素抵抗和动脉粥样硬化。此外，代谢综合征是与年龄相关的痴呆的一个危险因素。本研究的重点是MyD88的作用，它是细胞因子和Toll样受体信号传递所必需的。我们发现，髓细胞选择性删除MyD88实际上消除了肥胖小鼠饮食诱导的代谢综合征。在这里，我们将这项研究扩展到炎症信号对有或没有代谢综合征的衰老肥胖小鼠与年龄相关的认知能力下降的影响。目前的建议提出了一个假设，即从所有CD11b+骨髓细胞中删除MyD88将改善肥胖但没有代谢综合征的小鼠的年龄相关认知障碍。此外，我们提出，从小胶质细胞中选择性删除MyD88也会减少代谢综合征小鼠的年龄相关认知障碍，而不会影响全身综合征。重要的是，MyD88在人类和小鼠中表现出功能同源，并且它的缺失不会引起不可接受的免疫缺陷，这表明该途径可能是可药物治疗的。具体目标是：1。确定高脂饮食（HFD）中MyD88fl/fl::CD11bCre小鼠代谢综合征的改善是否与年龄相关认知变化的改善有关。将MyD88fl/fl::CD11bCre小鼠置于HFD或食物中，进行一系列行为测试和海马长期增强（LTP）。将进行外周和中枢神经系统组织的病理分析。这些数据将探讨是否通过阻断骨髓细胞的先天免疫反应和系统性地减少代谢综合征来改善HFD喂养的衰老小鼠的认知能力下降。2. 确定他莫昔芬注射MyD88fl/fl::CX3CR1(ER)-Cre小鼠高脂饮食（HFD）是否能改善与年龄相关的认知变化。我们预计MyD88fl/fl::CD11bCre缺失骨髓细胞MyD88的小鼠与对照组相比，会表现出与年龄相关的认知能力的改善。然而，这些机制可以在系统中或在中枢神经系统中发挥作用，也可以两者兼而有之。CX3CR1(ER)-Cre驱动程序有效地从CX3CR1+细胞中删除“floxed”靶标，并且在诱导后约1个月，重组对小胶质细胞具有高度选择性。MyD88fl/fl::CX3CR1(ER)- Cre小鼠将接受他莫昔芬诱导重组，并将其置于HFD或饲料中。小鼠将接受一系列行为测试和海马LTP，如第1部分所示。将进行外周和中枢神经系统组织的集中病理和免疫组织化学分析。这些数据将解决衰老小鼠认知能力下降是否可以通过阻断小胶质细胞先天免疫来改善，尽管存在全身性代谢综合征。这些实验的数据将有助于我们了解代谢综合征相关炎症恶化衰老个体认知功能的系统和中枢神经系统机制，并将确定突出的外周和中枢神经系统治疗靶点。

DESCRIPTION (provided by applicant): Inflammation contributes to metabolic syndrome, including insulin resistance and atherosclerosis. Further, metabolic syndrome represents a risk factor for age-related dementias. This proposal focuses on the role of MyD88, required for signaling from cytokine and Toll Like Receptors. We showed that selective deletion of MyD88 from myeloid cells virtually eliminated diet-induced metabolic syndrome in obese mice. Here we extend this research to effects of inflammatory signaling for age-related cognitive decline in aging obese mice with or without metabolic syndrome. The present proposal addresses the hypothesis that deleting MyD88 from all CD11b+ myeloid cells will ameliorate age-related cognitive impairment in mice with obesity but without metabolic syndrome. Furthermore, we propose that selective deletion of MyD88 from microglia will also reduce age-related cognitive impairment in mice with metabolic syndrome, without affecting the systemic syndrome. Importantly, MyD88 appears functionally orthologous in humans and mice, and its absence does not cause unacceptable immunodeficiency suggesting the pathway is potentially druggable. The specific aims are: 1. Establish whether ameliorating metabolic syndrome in MyD88fl/fl::CD11bCre mice on high-fat diet (HFD) is associated with improvement of age-related cognitive change. MyD88fl/fl::CD11bCre mice will be placed on HFD or chow and undergo serial behavior testing as well as hippocampal long-term potentiation (LTP). Pathological analyses of peripheral and CNS tissues will be performed. These data will address whether declining cognition is ameliorated in aging mice fed HFD by blocking innate immune reactions of myeloid cells and reducing metabolic syndrome systemically. 2. Determine if reduced microglial reaction in tamoxifen-injected MyD88fl/fl::CX3CR1(ER)-Cre mice on high-fat diet (HFD) improves age-related cognitive change. We anticipate that MyD88fl/fl::CD11bCre mice lacking myeloid-cell MyD88 will show improved age-related cognition as compared to controls. The mechanisms however could be exerted either systemically, in the CNS or both. The CX3CR1(ER)-Cre driver efficiently deletes 'floxed' targets from CX3CR1+ cells, and recombination is highly-selective for microglia by about one month after induction. MyD88fl/fl::CX3CR1(ER)- Cre mice will receive tamoxifen to induce recombination and will be placed on HFD or chow. Mice will be subjected to serial behavior testing and hippocampal LTP as in Aim 1. Focused pathological and immunohistochemical analyses of the peripheral and CNS tissues will be performed. These data will address whether declining cognition in aging mice is ameliorated by blocking innate immunity in microglia despite systemic metabolic syndrome. Data from these experiments will contribute to our knowledge of the systemic and CNS mechanisms by which metabolic syndrome-associated inflammation worsens cognitive function in aging individuals and will identify salient peripheral and CNS treatment targets.