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

描述（由申请人提供）：神经炎症一直被认为是阿尔茨海默病（AD）病理的一致组成部分。我们对神经炎症参与阿尔茨海默病发病机制的理解已经发生了变化：多年来，人们认为它会驱动斑块和缠结病理，并导致神经退行性变；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A -积累的控制很重要。在该基金支持的研究中，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 α加工的改变。我们有进一步的数据表明，该过程不依赖于募集外周表达髓细胞的CCR2。相反，我们发现持续的IL-1表达导致精氨酸酶-1阳性小胶质细胞的积累，这些小胶质细胞产生于局部小胶质细胞，并且似乎具有吞噬聚集的A的能力；初步数据还表明，IL-4在慢性神经炎症模型中升高。总之，这些发现支持了一种新的假设，即AD中由IL-1持续表达引起的慢性神经炎症通过IL-4依赖的内源性小胶质细胞的替代激活来减少斑块的积累。在3xTgAD和JNPL3小鼠模型中的进一步研究揭示了IL-1表达对tau病理的负面影响，并提出了一种假设，即对淀粉样蛋白的慢性神经炎症反应有助于控制斑块积聚，从而导致tau病理增强。慢性神经炎症对阿尔茨海默病病理过程的不同影响可能有助于解释旨在调节炎症治疗阿尔茨海默病的临床研究令人失望的结果。然而，他们认为慢性神经炎症的成分可以选择性地调节，以减少斑块积累，而不影响tau磷酸化。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小鼠中验证选择性激活的精氨酸酶-1阳性小胶质细胞参与淀粉样蛋白清除。我们还将确定模型系统中精氨酸酶-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，以更好地了解与慢性神经炎症相关的促炎和抗炎细胞因子、趋化因子和细胞变化之间的平衡，并在人AD组织中开展类似的研究。此外，我们将确定IL-4的细胞来源

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.