REGULATION OF NEUROINFLAMMATION BY ApoE AND ApoE RECEPTORS

大量激活的胶质细胞(小胶质细胞和星形胶质细胞)是许多神经退行性疾病的共同病理特征，包括阿尔茨海默病(AD)，在淀粉样斑块周围发现激活的胶质细胞。载脂蛋白E(ApoE)也与这些斑块相关，主要由神经胶质细胞合成和分泌。在体外，我们已经证明了淀粉样β蛋白(Abeta)诱导胶质细胞激活以及内源性apoE的增加，从而限制了炎症反应。我们还证明了载脂蛋白E受体介导了 Abeta诱导的胶质细胞活化和载脂蛋白E的增加。因此，我们的假设是apoE是一种内源性抗炎蛋白，由激活的胶质细胞通过apoE受体介导的机制作为对Abeta的独特反应而产生。这种Abeta诱导的载脂蛋白E增加作为一种负反馈反应，限制了进一步的胶质细胞激活。这一过程的中断可能会导致无调控的神经炎症，从而导致神经退行性事件。这项拨款的总体目标是确定Abeta与载脂蛋白E受体相互作用的途径，以诱导胶质细胞激活和增加载脂蛋白E。此外，我们还将在体外和体内确定这一胶质细胞介导的过程对神经元活性的影响。本研究的具体目的包括：1.确定寡聚体和纤维状Abeta1-42对神经胶质细胞活化、载脂蛋白E水平和神经元活力的影响。假设：寡聚体Abeta1-42是比纤维状Abeta1-42更有效的神经胶质激活诱导剂。2.确定Aβ诱导神经胶质细胞活化的机制。假设：脂蛋白受体相关蛋白(LRP)介导Abeta诱导的神经胶质细胞激活。3.确定Abeta诱导载脂蛋白E升高的机制。假设：低密度脂蛋白受体(LDLR)介导Abeta诱导的载脂蛋白E增加。4.明确载脂蛋白E抗炎活性的模式和异构体特异性。假设：ApoE4是一种不如APOE2或E3有效的抗炎药。这项资助旨在确定Abeta、apoE受体和apoE如何相互作用来调节神经胶质细胞的激活。抑制神经胶质细胞介导的炎症反应可能是载脂蛋白E和载脂蛋白E受体维持神经元活性的一种方式。此外，如果apoE4是一种不如APOE2或E3有效的抗炎药，这种活性将解释epsilon 4与AD之间的相关性。了解载脂蛋白E受体介导的Abeta诱导胶质细胞激活和apoE拮抗这一过程的机制可能为干预神经炎性和 神经退行性变过程。

Large numbers of activated glia (microglia and astrocytes) are a common pathological feature of many neurodegenerative disorders, including Alzheimer's disease (AD) where activated glia are found surrounding amyloid plaques. Apolipoprotein E (apoE) is also found associated with these plaques and is synthesized and secreted primarily by glial cells. In vitro, we have demonstrated amyloid-beta (Abeta) induces glial activation as well as an increase in endogenous apoE that acts to limit the inflammatory response. We have also demonstrated that apoE receptors mediate both Abeta-induced glial activation and the increase in apoE. Thus, our hypothesis is that apoE is an endogenous antiinflammatory protein produced by activated glia as a unique response to Abeta via a mechanism mediated by apoE receptors. This Abeta-induced increase in apoE serves as a negative feedback response to limit further glial activation. Disruption of this process may contribute to unregulated neuroinflammation leading to neurodegenerative events. The overall goal of this grant is to define the pathway whereby Abeta interacts with apoE receptors to induce glia activation and increase apoE. In addition, we will determine the effect of this glial-mediated process on neuronal viability in vitro and in vivo. The specific aims for this proposal include: 1. Determine the effect of oligomeric and fibrillar Abeta1-42 on glial activation, apoE levels and neuronal viability. Hypothesis: Oligomeric Abeta1-42 is a more potent inducer of glial activation than fibrillar Abeta1-42. 2. Determine the mechanism for Abeta-induced glial activation. Hypothesis: Lipoprotein receptor-related protein (LRP) mediates Abeta-induced glial activation. 3. Determine the mechanism for the Abeta-induced increase in apoE. Hypothesis: Low-density lipoprotein receptor (LDLR) mediates Abeta-induced increases in apoE. 4. Define the pattern and isoform-specificity of apoE's anti-inflammatory activity. Hypothesis: ApoE4 is a less efficient anti-inflammatory agent than apoE2 or E3. This grant is designed to determine how Abeta, apoE receptors, and apoE interact to regulate glial activation. Inhibition of the glial-mediated inflammatory response may be one way that apoE and apoE receptors preserve neuronal viability. In addition, if apoE4 is a less efficient anti-inflammatory agent than apoE2 or E3, this activity would account for the correlation between epsilon4 and AD. Understanding the apoE receptor-mediated mechanisms whereby Abeta induces glial cell activation and apoE antagonizes the process may provide additional sites for intervening in neuroinflammatory and neurodegenerative processes.