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

摘要 人类全基因组关联研究和阿尔茨海默病动物模型的工作已经开始揭示 TREM 2，CD 33和CD 22在阿尔茨海默病和其他形式的年龄相关性痴呆中的关键作用。而 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 尽管进展缓慢，但我们仍然缺乏对这些细胞所采用的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。参与的信号通路的鉴定 对阿尔茨海默病的免疫反应将有助于揭示新的治疗靶点， 深入了解神经退行性疾病的病因。SYK-CARD 9信号传导轴已被证明 在其他疾病模型中控制TREM 2、CD 33和CD 22下游的免疫应答，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 初步研究，我们发现在淀粉样蛋白β（Ab）介导的小鼠中CARD 9的基因消融 阿尔茨海默病模型导致认知能力下降加剧，Ab沉积增加， 激活小胶质细胞。我们还表明，CARD 9或SYK的破坏导致对细胞的吞噬功能受损。 抗体和其他形式的神经毒性碎片与神经变性。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，巨噬细胞的Ab刺激促进了有效的 激活SYK信号。鉴于这些初步发现和其他显示SYK和CARD 9是 几乎完全由大脑中的小胶质细胞表达，我们假设SYK-CARD 9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Ab介导的神经疾病。 利用独特的转基因小鼠品系和人类诱导的多能干细胞的组合， 从携带CARD 9功能丧失突变的患者中，我们将揭示SYK-CARD 9信号轴如何 影响AD小鼠模型中的神经系统疾病。此外，我们将测试是否治疗与 已知的SYK-CARD 9信号传导途径的激活剂有效限制Ab介导的疾病进展。 完成本申请中提出的研究将在我们对 先天免疫系统在抗体介导的神经系统疾病中使用的分子信号传导途径， 帮助建立新的分子参与者，可以在阿尔茨海默病的目标。

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.