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.

AD的不同病理学包括淀粉样蛋白-b（Ab）的细胞外沉积、淀粉样蛋白-b（Ab）的细胞内积累、淀粉样蛋白-b（Ab）的细胞外沉积和淀粉样蛋白-b（Ab）的细胞内积累。 过度磷酸化的tau蛋白和广泛的神经炎症。尽管有基因证据表明抗体驱动 阿尔茨海默氏病（AD）病理学，免疫疗法和分泌酶抑制剂干预的努力， 基本上都失败了，这表明淀粉样蛋白假说不足以解释整个病理过程。 相反，越来越多的证据揭示了这三种病理的交织，它们共同驱动了 导致痴呆的突触丧失和神经断开。我们的工作和其他人的工作支持一个模型， 其中神经炎症将淀粉样蛋白和tau病理联系起来，并且可以直接导致突触丢失、血管损伤和神经损伤。 功能障碍和氧化损伤。小胶质细胞是神经炎症的重要驱动因素， 神经退行性疾病中的表型变化并表达疾病相关的小胶质细胞（DAM）基因， 包括一些被认为是AD的风险因素（例如TREM 2和ApoE）。因此，靶向小胶质细胞激活 代表了AD和其他神经退行性疾病的一种重要的潜在治疗方法。一 鉴定的DAM是Axl，其是在AD中上调的受体酪氨酸激酶，特别是在与AD相关的小胶质细胞中。 淀粉样斑块Axl的配体，生长停滞特异性蛋白6（Gas 6）的结合具有多模式效应， 包括启动吞噬作用和抑制炎症。尽管Axl的关联- Axl表达具有淀粉样沉积物的小胶质细胞，Axl在Ab吞噬作用中的作用尚不清楚， 小胶质细胞Axl信号传导改变炎性环境和其它AD病理学如tau。基于 在我们的初步研究中，我们假设用Gas 6激活Axl信号传导可用于增加Ab 吞噬和抑制炎症，对其他疾病相关终点产生有益影响 如tau蛋白磷酸化和认知功能障碍。这个想法，以及随之而来的假设， 将在APP/PS1和P301 S tau小鼠以及原代小胶质细胞中测试 利用遗传学和药理学方法进行培养。我们提出的实验将提供基础知识 关于Gas 6：Axl信号在小胶质细胞中的作用的信息，并帮助确定是否调节Axl活性 提供了一种使用临床前模型的易处理的AD治疗方法。