Microglia, RAGE, and Alzheimer's Disease

阿尔茨海默病（AD）是一种神经退行性疾病，目前无法治愈，影响数百万人， 世界各地的人们。虽然AD的主要危险因素是衰老，但基因组技术的新进展涉及到 小胶质细胞（大脑的巨噬细胞）中的炎症脂质信号传导是认知能力下降的驱动力 在AD中。然而，尽管有这些观察结果，小胶质细胞发炎的具体机制 和脓毒症加剧AD脑内的神经毒性是未知的。因此，至关重要的是 发展我们对控制小胶质细胞对神经元健康影响的分子的理解， 退化越来越多的证据表明，晚期糖基化终产物受体的关键作用 （3）调节AD期间的小胶质细胞炎症。β-内酰胺酶是一种免疫球蛋白型细胞表面受体 其在CNS和外周的许多细胞类型上表达，包括小胶质细胞和巨噬细胞。它 结合多种配体，包括：糖化蛋白和脂质、S100/钙颗粒蛋白、寡聚Aβ、高 迁移率族蛋白1（HMGB 1）和磷脂酰丝氨酸（PS）。已知该受体介导强效 慢性疾病期间巨噬细胞中的炎症，其中已知病理配体家族 异常积累。然而，有趣的是，ESTA也可以调节稳态吞噬凋亡细胞， 细胞和蛋白质碎片。为了探讨AD和内环境稳定过程中小胶质细胞中BMP 1的作用，我们 已经在对照和AD样背景下产生了新的（CX 3CR 1 CreERT 2，CX 3CR 1/CX 3CR 1/CX 3CR 1）小鼠。因此，在本发明中， 在成年小鼠中，在不同的生长期，在他莫昔芬诱导后， 煽动性的背景。我们的首要假设是信号转导在环境中起作用- 在小胶质细胞中的依赖性双重和对立作用。在体内平衡过程中， 神经胶质细胞参与适应性小胶质细胞迁移、吞噬作用和炎症反应;在高密度的环境中， β-淀粉样蛋白配体的水平，β-淀粉样蛋白驱动小胶质细胞中的损伤性炎症和氧化应激， 从而引发神经元和突触功能障碍以及不可逆的认知衰退。超出 新一代的模型，我们已经开发出一种技术，分离可行的，高纯度的，成人小胶质细胞， 以探测关键的小胶质细胞调节分子和离体吞噬作用。我们将展示这些模型， 分离，以探讨在AD的稳态（Aim 1）和不同阶段， 进展（目标2）。最后，为了进一步阐明小胶质细胞的作用，我们将用激光诱导 活体小鼠和图像对照的皮质中的消融损伤和RAGE缺乏的YFP+小胶质细胞迁移 向受伤部位移动（目标3）。通过这些实验，我们将阐明我们所知甚少的 在体内平衡和神经炎性反应中， 应力在这样做的过程中，这项工作将为神经炎性疾病的治疗策略提供信息， 特别是阿尔茨海默病

Alzheimer's disease (AD) is a neurodegenerative disorder that currently has no cure and impacts millions of people worldwide. While the primary risk factor for AD is aging, new advances in genomic technology implicate inflammatory lipid signaling in microglia, the macrophages of the brain, as a driving force for cognitive decline in AD. However, despite these observations, the specific mechanisms by which microglia become inflamed and putatively exacerbate neurotoxicity within the AD brain are unknown. Thus, it is critically important to develop our understanding of the molecules that govern the impact of microglia on neuronal health and degeneration. Mounting evidence suggests a critical role for the Receptor for Advanced Glycation Endproducts (RAGE) in regulating microglia inflammation during AD. RAGE is an immunoglobulin-type, cell surface receptor that is expressed on numerous cell types in the CNS and periphery, including microglia and macrophages. It binds a diverse class of ligands, including: glycated proteins and lipids, S100/calgranulins, oligomeric Aβ, high mobility group box 1 (HMGB1), and phosphatidylserine (PS). This receptor is known to mediate potent inflammation in macrophages during chronic diseases, in which pathological ligands families are known to aberrantly accumulate. However, intriguingly, RAGE may also regulate homeostatic phagocytosis of apoptotic cells and protein debris. In order to probe the effects of RAGE in microglia during homeostasis and AD, we have generated novel (CX3CR1 CreERT2, RAGE flox/flox) mice in control and AD-like backgrounds. Thus, RAGE can be specifically deleted from microglia after tamoxifen induction in adult mice during diverse inflammatory contexts. Our overarching hypothesis is that RAGE signal transduction plays context- dependent dual and opposing roles in microglia. In low levels of RAGE ligands during homeostasis, RAGE contributes to adaptive microglia migration, phagocytosis and inflammation; in milieus of high levels of RAGE ligands, RAGE drives damaging inflammatory and oxidative stress in microglia, thereby triggering neuronal and synaptic dysfunction, and irreversible cognitive decline. Beyond the generation of novel models, we have developed a technique to isolate viable, highly pure, adult microglia in order to probe key microglia regulatory molecules and phagocytosis ex vivo. We will utlize these models and isolates to probe how RAGE alters microglia function during homeostasis (Aim 1) and distinct phases of AD progression (Aim 2). Finally, in order to further delineate the role of microglia RAGE, we will induce laser ablation injuries in the cortex of live mice and image control and RAGE-devoid YFP+ microglia migrating towards the site of injury (Aim 3). Through these experiments, we will elucidate the poorly understood mechanisms by which RAGE modulates microglia responses during homeostasis and neuroinflammatory stress. In doing so, this work will inform therapeutic strategies in the treatment of neuroinflammatory disease, specifically Alzheimer's disease.