Microglia, RAGE, and Alzheimer's Disease

小胶质细胞、RAGE 和阿尔茨海默病

• 批准号: 9335649
• 负责人: Julia Derk
• 金额: $ 3.5万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9335649
• 关键词: Ablation; Acute; Adult; Advanced Glycosylation End Products; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease risk; Amyloid beta-Protein; Anti-inflammatory; Apoptotic; Automobile Driving; Autopsy; Behavioral; Binding; Biochemical; Blood - brain barrier anatomy; Brain; Brain Diseases; Cell Surface Receptors; Cells; Cellular Stress; Cholesterol; Cholesterol Homeostasis; Chronic Disease; Cognition; Data; Dendritic Spines; Deposition; Disease; Disease Progression; Dose; Family; Functional disorder; Generations; Genetic; Genomics; HMGB1 Protein; Health; Homeostasis; Image; Immune; Immunoglobulins; Immunohistochemistry; Impaired cognition; Impairment; Inflammation; Inflammation Mediators; Inflammatory; Injury; Lasers; Learning; Leukocyte L1 Antigen Complex; Life; Ligand Binding; Ligands; Link; Lipids; Maintenance; Mediating; Microglia; Modeling; Molecular; Molecular Profiling; Mus; Mutation; Natural regeneration; Nerve Degeneration; Neuraxis; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Outcome; Oxidative Stress; Pathologic; Pattern; Permeability; Phagocytes; Phagocytosis; Phase; Phase III Clinical Trials; Phenotype; Phosphatidylserines; Play; Production; Proteins; Reactive Oxygen Species; Receptor Gene; Risk Factors; Role; Senile Plaques; Shapes; Signal Transduction; Signaling Molecule; Site; Specificity; Stress; Surface Immunoglobulins; Synapses; Synaptic plasticity; Tamoxifen; Techniques; Technology; Testing; Therapeutic; Therapeutic Intervention; Tissues; Toxic effect; Work; acute stress; aged; burden of illness; cell motility; cell type; cytokine; driving force; environmental enrichment for laboratory animals; experimental study; genetic association; in vivo two-photon imaging; inflammatory marker; inhibitor/antagonist; macrophage; migration; molecular phenotype; mouse model; neuroinflammation; neuron loss; neuronal circuitry; neurotoxic; neurotoxicity; new therapeutic target; novel; phase II trial; receptor; receptor for advanced glycation endproducts; receptor function; regenerative; repaired; response; synaptogenesis; tau Proteins

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.

阿尔茨海默病(AD)是一种神经退行性疾病，目前尚无治愈方法，影响数百万人 世界各地的人们。虽然阿尔茨海默病的主要风险因素是衰老，但基因组技术的新进展表明 脑内巨噬细胞--小胶质细胞的炎性脂质信号是认知功能减退的驱动力 在公元后。然而，尽管有这些观察，小胶质细胞发炎的具体机制 以及可能加剧阿尔茨海默病脑内神经毒性的原因尚不清楚。因此，至关重要的是， 发展我们对小胶质细胞对神经元健康的影响的分子的理解 退化。越来越多的证据表明晚期糖基化终末产物受体的关键作用 (RAGE)在AD过程中调节小胶质细胞炎症。RAGE是一种免疫球蛋白型细胞表面受体 它在中枢神经系统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 结合不同类别的配体，包括糖化蛋白和脂类、S100/钙颗粒蛋白、寡聚体Aβ、高 运动基团蛋白1(HMGB1)和磷脂酰丝氨酸(PS)。已知这种受体能有效地介导 慢性疾病期间巨噬细胞的炎症，其中病理配体家族已知 反常地积累。然而，有趣的是，RAGE也可能调节细胞凋亡的稳态吞噬作用 细胞和蛋白质碎片。为了探讨RAGE在动态平衡和AD过程中对小胶质细胞的影响，我们 在对照组和AD样背景中产生了新的(CX3CR1 CreERT2，RAGE FLOX/FLOX)小鼠。因此， 成年小鼠经他莫昔芬诱导后，在不同的时间段，RAGE可以从小胶质细胞中特异性地删除 炎症性环境。我们的主要假设是愤怒信号转导在上下文中起作用- 小胶质细胞中依赖的双重角色和相反的角色。在动态平衡期间低水平的RAGE配体， RAGE有助于适应性小胶质细胞迁移、吞噬和炎症；在高环境中 RAGE配体的水平，RAGE驱动小胶质细胞的炎症和氧化应激损伤， 从而引发神经元和突触功能障碍，以及不可逆转的认知衰退。超越了 随着新模型的产生，我们已经开发出一种技术来分离存活的、高纯度的成年小胶质细胞 为了探索关键的小胶质细胞调节分子和体外吞噬功能。我们将利用这些模式和 分离以探索愤怒如何在AD的动态平衡(目标1)和不同阶段改变小胶质细胞功能 进展(目标2)。最后，为了进一步阐明小胶质细胞的作用，我们将诱导激光。 活体小鼠大脑皮质消融损伤与影像控制和无RAGE的YFP+小胶质细胞迁移 向受伤地点进发(目标3)。通过这些实验，我们将阐明那些鲜为人知的 RAGE在动态平衡和神经炎性反应中调节小胶质细胞反应的机制 压力。通过这样做，这项工作将为神经炎症性疾病的治疗策略提供参考， 尤其是阿尔茨海默病。