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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease pathology Alzheimer&apos 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

项目摘要

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的不同病理包括淀粉样蛋白B（AB）的细胞外沉积，细胞内积累高磷酸化的tau蛋白和广泛的神经炎症。尽管遗传证据表明AB驱动阿尔茨海默氏病（AD）病理学，干预免疫疗法和泌尿酶抑制剂的努力本质上都是失败的，表明淀粉样蛋白假说不足以解释完整的病理过程。取而代之的是，积累证据揭示了这三种病理的交织，这将驱动着引起痴呆的突触损失和神经跨连接。我们的工作和他人的工作支持模型哪种神经炎症将淀粉样蛋白和tau病理联系起来，可以直接导致合成损失，血管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，表现出戏剧性神经退行性疾病的表型变化和与疾病相关的小胶质细胞（DAM）基因，包括一些被公认为AD风险因素（例如TREM2和APOE）。那是针对小胶质激活的代表了AD和其他神经退行性疾病的重要潜在治疗方法。一已确定的大坝是Axl，Axl是一种受体酪氨酸激酶，在AD中进行了更新，特别是在相关的小胶质细胞中带有淀粉样斑块。 AXL配体的结合，生长避孕特异性蛋白6（GAS6）具有多模式作用，包括吞噬作用和炎症抑制的倡议。尽管Axl- 用淀粉样蛋白沉积表达小胶质细胞，Axl在AB吞噬作用中的作用尚不清楚，也不知道是否知道小胶质AXL信号传导修饰炎症环境和其他AD病理，例如TAU。基于我们的初步研究，我们假设使用GAS6的AXL信号激活可用于增加AB 吞噬作用和抑制注射，对其他疾病相关终点产生有益的作用例如tau磷酸化和认知功能障碍。这个想法以及AXL丧失的推论假设信号传导增加了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物方法进行培养。我们提出的实验将提供基本有关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活性使用临床前模型为AD提供了可拖动的治疗方法。