Gas6:Axl regulation of microglia immune function and Alzheimer's pathogenesis

Gas6：Axl对小胶质细胞免疫功能和阿尔茨海默病发病机制的调节

• 批准号: 10229210
• 负责人: Michael Rusty Elliott
• 金额: $ 51.3万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10229210
• 关键词: APP-PS1; Abeta clearance; Activities of Daily Living; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease risk; Amyloid; Amyloid beta-Protein; Amyloid deposition; Apolipoprotein E; Behavior; Behavioral; Binding; Biological Assay; Cognitive deficits; Data; Dementia; Deposition; Disease; Genes; Genetic; Growth; Hippocampus (Brain); Immunotherapy; Impaired cognition; In Vitro; Inflammation; Language; Lead; Ligands; Link; LoxP-flanked allele; Mediating; Memory Loss; Microglia; Modeling; Molecular; Mus; Myeloid Cells; Nerve Degeneration; Neurodegenerative Disorders; Neuronal Dysfunction; Pathogenesis; Pathologic; Pathology; Phagocytes; Phagocytosis; Pharmacology; Phenotype; Phosphorylation; Population; Pre-Clinical Model; Property; Proteins; Receptor Protein-Tyrosine Kinases; Receptor Signaling; Regulation; Role; Senile Plaques; Signal Transduction; Synapses; TREM2 gene; Testing; Therapeutic; Transgenic Mice; Vascular Diseases; Work; base; executive function; experimental study; extracellular; genetic approach; hyperphosphorylated tau; immune function; in vivo; inflammatory milieu; inhibitor/antagonist; mouse model; multimodality; neuroinflammation; neuropathology; oxidative damage; pre-clinical; receptor; relating to nervous system; secretase; tau Proteins; tau aggregation; tau phosphorylation; therapeutic target; vector; β-amyloid burden

The distinct pathology of AD includes extracellular deposits of amyloid-b (Ab), intracellular accumulation of hyperphosphorylated tau protein, and wide-spread neuroinflammation. Despite genetic evidence that Ab drives Alzheimer’s disease (AD) pathology, efforts to intervene with immunotherapies and secretase inhibitors have essentially all failed, indicating that the amyloid hypothesis is not sufficient to explain the full pathological course. Instead, accumulating evidence reveals an intertwining of these three pathologies, which together drive the synaptic loss and neural disconnection that lead to dementia. Our work and that of others supports a model in which neuroinflammation links amyloid and tau pathology, and can directly contribute to synaptic loss, vascular dysfunction, and oxidative damage. Microglia are essential drivers of neuroinflammation that show dramatic phenotypic changes in neurodegenerative diseases and express disease-associated microglial (DAM) genes, including some recognized as risk factors for AD (e.g. TREM2 and ApoE). Thus, targeting microglial activation represents an important potential therapeutic approach to AD and other neurodegenerative conditions. One identified DAM is Axl, a receptor tyrosine kinase that is upregulated in AD, particularly in microglia associated with amyloid plaques. Binding of Axl’s ligand, growth-arrest specific protein 6 (Gas6) has multimodal effects that include both initiation of phagocytosis and suppression of inflammation. Despite the association of Axl- expressing microglia with amyloid deposits, Axl’s role in Ab phagocytosis is not known, nor is it known whether microglial Axl signaling modifies the inflammatory environment and other AD pathologies such as tau. Based on our preliminary studies, we hypothesize that activation of Axl signaling with Gas6 can be used to increase Ab phagocytosis and suppress inflammation, providing a beneficial effect on other disease-associated endpoints such as tau phosphorylation and cognitive dysfunction. This idea, and the corollary hypothesis that loss of Axl signaling increases AD pathology, will be tested in APP/PS1 and P301S tau mice as well as in primary microglial cultures using genetic and pharmacologic approaches. Our proposed experiments will provide fundamental information about the role of Gas6:Axl signaling in microglia, and help determine whether modulating Axl activity provides a tractable therapeutic approach for AD using preclinical models.

阿尔茨海默病的独特病理包括细胞外淀粉样蛋白b(Ab)的沉积，细胞内淀粉样蛋白b的积聚。 过度磷酸化的tau蛋白，以及广泛的神经炎症。尽管有遗传证据表明，抗体驱动 阿尔茨海默病(AD)的病理，免疫疗法和分泌酶抑制剂的干预努力 基本上都失败了，这表明淀粉样蛋白假说不足以解释完整的病理过程。 相反，越来越多的证据揭示了这三种病理的相互交织，这三种病理共同推动了 导致痴呆的突触丢失和神经断开。我们和其他人的工作支持一个模型 神经炎症将淀粉样蛋白和tau蛋白的病理联系起来，并可直接导致突触丢失、血管 功能障碍和氧化损伤。小胶质细胞是神经炎症的基本驱动因素，表现出戏剧性的 神经退行性疾病的表型变化和表达疾病相关小胶质细胞(DAM)基因， 包括一些公认为AD的危险因素(如TREM2和ApoE)。因此，靶向小胶质细胞激活 代表了治疗AD和其他神经退行性疾病的一种重要的潜在治疗方法。一 确认的DAM是Axl，一种受体酪氨酸激酶，在AD中上调，特别是在相关的小胶质细胞中 有淀粉样斑块。AXL的配体，生长抑制特定蛋白6(Gas6)的结合具有多峰效应， 包括启动吞噬和抑制炎症。尽管AXL- 表达淀粉样蛋白沉积的小胶质细胞，Axl在抗体吞噬中的作用尚不清楚，也不知道是否 小胶质细胞Axl信号改变炎症环境和其他AD病理，如tau。基于 我们的初步研究，我们假设AXL信号与Gas6的激活可以用来增加抗体 吞噬和抑制炎症，对其他疾病相关的终末点提供有益的影响 例如tau的磷酸化和认知功能障碍。这个想法，以及由此而来的假设，即AXL的损失 信号增加AD病理，将在APP/PS1和P301S tau小鼠以及原代小胶质细胞中进行测试 使用遗传和药理学方法的培养。我们提议的实验将提供基本的 关于Gas6：Axl信号在小胶质细胞中的作用的信息，并有助于确定是否调节Axl的活性 使用临床前模型为AD提供一种易于处理的治疗方法。