Role of the SYK-CARD9 signaling axis 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。

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.