Mechanism of IL-1 Dependent A-beta Plaque Clearance in Alzheimer's Disease

描述（由申请人提供）：神经炎症长期以来被认为是阿尔茨海默病（AD）病理学的一致组成部分。我们对神经炎症参与AD发病机制的理解已经发展：多年来，它被认为是驱动斑块和缠结病理，并有助于神经退行性变;然而，最近的证据揭示了神经炎症的复杂作用。事实上，我们自己的研究结果表明，与AD相关的慢性神经炎症对于控制A？积累很重要。在这项资助支持的研究中，我们发现持续的白细胞介素-1（IL-1）表达导致APP/PS-1小鼠斑块病理学显著减少，并且与斑块周围小胶质细胞的积累有关，而不是A？处理的变化。我们有进一步的数据表明，该过程不依赖于外周CCR 2表达骨髓细胞的募集。相反，我们发现持续的IL-1表达导致从局部小胶质细胞产生的α-淀粉酶-1阳性小胶质细胞的积累，并且似乎具有吞噬聚集的A？的能力;初步数据还表明，IL-4在我们的慢性神经炎症模型中升高。总之，这些发现支持了新的假设，即AD中持续IL-1表达引起的慢性神经炎症通过内源性小胶质细胞的IL-4依赖性替代激活减少斑块积聚。在3xTgAD和JNPL 3小鼠模型中的其他研究揭示了IL-1表达对tau病理学的负面影响，并提出了以下假设：对淀粉样蛋白的慢性神经炎症反应有助于控制斑块积聚，导致tau病理学增强。慢性神经炎症对AD病理过程的这种差异性作用可能有助于解释旨在调节炎症用于AD治疗的临床研究的令人失望的结果。然而，他们提出了慢性神经炎症的组分可以选择性地调节以减少斑块积累而不影响tau磷酸化的可能性。为了探索这些想法，我们将：1）在患有慢性神经炎症的APP/PS-1小鼠中，验证交替激活的β-淀粉酶-1阳性小胶质细胞在淀粉样蛋白清除中的参与。我们还将确定在我们的模型系统中的p53 -1阳性细胞的来源。2)表征IL-1持续表达后的分子和细胞环境，以更好地了解促炎和抗炎细胞因子、趋化因子以及与慢性神经炎症相关的细胞变化之间的平衡，并对人类AD组织进行类似研究。此外，我们将通过以下方法鉴定IL-4的细胞来源： 在IL-4报告小鼠中过表达IL-1。3)在具有IL-4靶向缺失的APP/PS-1小鼠中持续表达IL-1后，以及通过在APP/PS-1小鼠中表达IL-4，评估IL- 4对替代活化和淀粉样蛋白吞噬作用的需求。4)在3xTgAD小鼠中使用IL-4表达载体，以确定淀粉样蛋白清除是否发生而不增加tau磷酸化。这些目标将有助于我们更好地了解慢性神经炎症在调节AD的两个标志性病理学中的作用。此外，他们还测试了选择性靶向淀粉样斑块清除的治疗干预的可能策略。这可能最终代表了一种比目前基于免疫的AD疗法更具选择性的方法。

DESCRIPTION (provided by applicant): Neuroinflammation has long been recognized as a consistent component of Alzheimer's disease (AD) pathology. Our understanding of neuroinflammation's involvement in AD pathogenesis has evolved: for years it was believed to drive plaque and tangle pathology and contribute to neurodegeneration; however, recent evidence reveals a complex role for neuroinflammation. Indeed, our own findings suggest that chronic neuroinflammation associated with AD is important for control of A¿ accumulation. In studies supported by this grant we found that sustained interleukin-1 (IL-1) expression led to significant reduction of plaque pathology in APP/PS-1 mice and was associated with accumulation of microglia around plaques rather than changes in A¿ processing. We have further data that the process does not depend on recruitment of peripheral CCR2 expressing myeloid cells. Instead, we find that sustained IL-1 expression leads to an accumulation of arginase-1 positive microglia that arise from local microglia, and which appear to have the capacity to phagocytize aggregated A¿; Preliminary data also suggests that IL-4 is elevated in our chronic model of neuroinflammation. Together, these findings support the new hypothesis that chronic neuroinflammation arising from sustained IL-1 expression in AD reduces plaque accumulation through IL-4 dependent alternative activation of endogenous microglial cells. Additional studies in the 3xTgAD and JNPL3 mouse models reveal a negative impact of IL-1 expression on tau pathology and suggest the hypothesis that the chronic neuroinflammatory response to amyloid, which helps to control plaque accumulation, leads to enhanced tau pathology. This differential effect of chronic neuroinflammation on pathological processes in AD may help to explain the disappointing results of clinical studies aimed at modulating inflammation for AD therapy. However, they suggest the possibility that components of chronic neuroinflammation can be selectively modulated to reduce plaque accumulation without affecting tau phosphorylation. To explore these ideas we will: 1) Verify the involvement of alternatively activated, arginase-1 positive microglia in amyloid clearance, in APP/PS-1 mice with chronic neuroinflammation. We will also determine the origin of arginase-1 positive cells in our model system. 2) Characterize the molecular and cellular environment following sustained IL-1 expression to better understand the balance between pro- and anti-inflammatory cytokines, chemokines, and cellular changes associated with chronic neuroinflammation and carry out similar studies with human AD tissues. In addition, we will identify the cellular source of IL-4 by overexpressing IL-1 in an IL-4 reporter mouse. 3) Assess the requirement of IL- 4 for alternative activation and amyloid phagocytosis following sustained IL-1 expression in APP/PS-1 mice with a targeted deletion of IL-4, and by expressing IL-4 in APP/PS-1 mice. 4) Utilize an IL-4 expression vector in the 3xTgAD mouse to determine whether amyloid clearance occurs without increased tau phosphorylation. Together these aims will help us to better understand the role of chronic neuroinflammation in modulating the two hallmark pathologies of AD. Moreover, they also test a possible strategy for therapeutic intervention that selectively targets amyloid plaque clearance. This may ultimately represent a more selective approach than current immune-based therapies for AD.