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Role of the SYK-CARD9 signaling axis in Alzheimer's disease

SYK-CARD9 信号轴在阿尔茨海默病中的作用

基本信息

批准号：
10198453
负责人：
John R Lukens
金额：
$ 158.67万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10198453
关键词：
Abeta clearance Ablation Affect Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease patient Amyloid beta-Protein Animal Disease Models Brain CD22 gene Cell Death Cell Line Cells Cognition Cognitive deficits Dementia Disease Disease Progression Disease model Experimental Models Genetic Human Human Genome Immune response Immune signaling Immunologic Receptors Impaired cognition Impairment In Vitro Individual Infection Innate Immune Response Innate Immune System Knowledge Mediating Mediator of activation protein Microglia Modeling Molecular Mouse Strains Mus Mutation Nerve Degeneration Neurodegenerative Disorders Pathogenesis Pathology Pathway interactions Patients Phagocytosis Pharmacology Phosphotransferases Production Role SYK gene Senile Plaques Signal Pathway Signal Transduction Signaling Molecule System TREM2 gene Testing Therapeutic Transgenic Mice Treatment Efficacy Work abeta deposition age related autoinflammatory cytokine genome wide association study in vivo induced pluripotent stem cell inhibitor/antagonist insight interest loss of function loss of function mutation macrophage mouse model nervous system disorder neuroinflammation neuropathology neurotoxic new therapeutic target novel protective effect receptor response transcriptomics

项目摘要

ABSTRACT Human genome-wide association studies and work in Alzheimer’s disease animal models have begun to uncover pivotal roles for TREM2, CD33, and CD22 in Alzheimer’s disease and other forms of age-related dementia. While increasing evidence indicates that these innate immune receptors are critically involved in Alzheimer’s disease progression, we still lack in-depth understanding of the intracellular signaling molecules employed by these immune receptors to influence neurodegenerative disease. Identification of the signaling pathways involved in the immune response to Alzheimer’s disease will help to reveal novel therapeutic targets and also provide new insights into neurodegenerative disease pathoetiology. The SYK-CARD9 signaling axis has been shown to control immune responses downstream of TREM2, CD33, and CD22 in other models of disease, although its role in Alzheimer’s disease and most other neurodegenerative disorders still remains to be determined. In our preliminary studies, we have found that genetic ablation of CARD9 in an amyloid beta (Ab)-mediated mouse model of Alzheimer’s disease results in exacerbated cognitive decline, increased Ab deposition, and impaired activation of microglia. We also show that disruption of either CARD9 or SYK leads to impaired phagocytosis of Ab and other forms of neurotoxic debris associated with neurodegeneration. In further support of a role for SYK in Alzheimer’s disease, recent in vitro studies have shown that Ab stimulation of macrophages promotes potent activation of SYK signaling. Given these preliminary findings and others showing that SYK and CARD9 are almost exclusively expressed by microglia in the brain, we hypothesize that the SYK-CARD9 signaling axis helps to limit Ab-mediated neurological disease by promoting neuroprotective functions in brain-resident macrophages. Leveraging a combination of unique transgenic mouse strains and human-induced pluripotent stem cells derived from patients harboring loss-of-function CARD9 mutations, we will uncover how the SYK-CARD9 signaling axis influences neurological disease in AD mouse models. Moreover, we will test whether therapeutic treatment with known activators of the SYK-CARD9 signaling pathway is effective in limiting Ab-mediated disease progression. Completion of the studies proposed in this application will break new ground in our understanding of the molecular signaling pathways used by the innate immune system in Ab-mediated neurological disease and will help to establish new molecular players that can be targeted in Alzheimer’s disease.

摘要阿尔茨海默病动物模型中的人类全基因组关联研究和工作已经开始发现 TREM2、CD33和CD22在阿尔茨海默病和其他形式的年龄相关痴呆中的关键作用。而当越来越多的证据表明，这些先天免疫受体与阿尔茨海默病密切相关进展，我们仍然缺乏对这些细胞内信号分子的深入了解免疫受体影响神经退行性疾病。细胞外信号转导通路的鉴定对阿尔茨海默病的免疫反应将有助于揭示新的治疗靶点，并提供新的对神经退行性疾病病因学的洞察。SYK-CARD9信号轴已被证明在其他疾病模型中控制TREM2、CD33和CD22下游的免疫反应，尽管其在阿尔茨海默病和大多数其他神经退行性疾病中的作用仍有待确定。在我们的初步研究发现，在淀粉样β蛋白(Ab)介导的小鼠中，CARD9的遗传消融阿尔茨海默病模型导致认知功能减退加剧，抗体沉积增加，并受损小胶质细胞的激活。我们还表明，CARD9或SYK的中断会导致细胞吞噬功能受损 AB和其他形式的与神经变性有关的神经毒性碎片。为了进一步支持SYK的作用在阿尔茨海默病中，最近的体外研究表明，抗体刺激巨噬细胞促进了 SYK信号的激活。鉴于这些初步发现以及其他显示SYK和CARD9是几乎完全由大脑中的小胶质细胞表达，我们假设SYK-CARD9信号轴有助于通过促进脑内巨噬细胞的神经保护功能来限制抗体介导的神经性疾病。利用独特的转基因小鼠品系和人类诱导的多潜能干细胞的组合从携带功能丧失CARD9突变的患者中，我们将揭示SYK-CARD9信号轴是如何影响阿尔茨海默病小鼠模型的神经系统疾病。此外，我们将测试治疗方法是否与已知的SYK-CARD9信号通路激活剂在限制抗体介导的疾病进展方面是有效的。完成本申请书所建议的研究，将会为我们对天然免疫系统在抗体介导的神经性疾病和Will中使用的分子信号通路帮助建立可针对阿尔茨海默病的新的分子玩家。