Loss of interleukin receptor-associated kinase 4 signaling suppresses amyloid pathology and alters microglial phenotype in a mouse model of Alzheimer's disease.
Loss of interleukin receptor-associated kinase 4 signaling suppresses amyloid pathology and alters microglial phenotype in a mouse model of Alzheimer's disease.
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DOI：
10.1523/jneurosci.1729-12.2012
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发表时间：
2012-10-24
期刊：
影响因子：
--
通讯作者：
Landreth GE
中科院分区：
文献类型：
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作者：
Cameron B;Tse W;Lamb R;Li X;Lamb BT;Landreth GE
阿尔茨海默病（Alzheimer's disease，AD）是一种典型的脑内淀粉样蛋白沉积，其引起强烈的小胶质细胞介导的炎症反应，与疾病恶化和加速进展相关。小胶质细胞是脑中的主要免疫效应细胞，并通过包括Toll样受体（TLR）2/4/6及其辅助受体的受体复合物与纤维状形式的Aβ（fAβ）相互作用。白细胞介素受体相关激酶（IRAK）是TLR信号转导所必需的细胞内信号分子。对单个TLR被敲除的AD小鼠模型的研究在TLR信号传导在淀粉样蛋白稳态中的作用方面产生了相互矛盾的结果。因此，我们破坏了一个常见的下游TLR信号元件IRAK 4。我们报道了小胶质细胞IRAK 4在体外是fAβ激活经典促炎信号通路所必需的，从而导致p38、JNK和ERK MAP激酶的激活并产生活性氧。在体内，IRAK 4功能的丧失导致AD鼠模型中Aβ水平降低。这与老年小鼠中小胶质细胞增生和星形胶质细胞增生减少有关。从成年小鼠脑中分离的小胶质细胞的分析揭示了与小胶质细胞表型变化相关的基因表达模式的改变，所述小胶质细胞表型变化与控制小胶质细胞表型的IRF转录因子的表达相关。此外，IRAK 4功能的丧失也促进淀粉样蛋白清除机制，包括胰岛素降解酶的表达升高。最后，阻断IRAK功能恢复嗅觉行为。这些数据表明，IRAK 4活化正常地调节小胶质细胞活化状态并影响脑中的淀粉样蛋白稳态。
Alzheimer’s disease (AD) typified the deposition of amyloid in the brain which elicits a robust microglial-mediated inflammatory response that is associated with disease exacerbation and accelerated progression. Microglia are the principal immune effector cells in the brain and interact with fibrillar forms of Aβ (fAβ) through a receptor complex that includes Toll-Like Receptors (TLR) 2/4/6 and their coreceptors. Interleukin receptor-associated kinases (IRAKs) are essential intracellular signaling molecules for transduction of TLR signals. Studies of mouse models of AD in which the individual TLRs are knocked out have produced conflicting results on roles of TLR signaling in amyloid homeostasis. Therefore, we disrupted a common downstream TLR signaling element, IRAK4. We report that microglial IRAK4 is necessary in vitro for fAβ to activate the canonical proinflammatory signaling pathways leading to activation of p38, JNK, and ERK MAP kinases and to generate reactive oxygen species. In vivo the loss of IRAK4 function results in decreased Aβ levels in a murine model of AD. This was associated with diminished microgliosis and astrogliosis in aged mice. Analysis of microglia isolated from the adult mouse brain revealed an altered pattern of gene expression associated with changes in microglial phenotype that were associated with expression of IRF transcription factors that govern microglial phenotype. Further, loss of IRAK4 function also promoted amyloid clearance mechanisms, including elevated expression of insulin degrading enzyme. Finally, blocking IRAK function restored olfactory behavior. These data demonstrate that IRAK4 activation acts normally to regulate microglial activation status and influence amyloid homeostasis in the brain.