A system approach to targeting innate immunity in AD

描述（由申请人提供）：阿尔茨海默病（AD）病理级联的一个不变特征是反应性神经胶质瘤，反映了大脑内先天免疫激活状态的潜在改变。先天免疫信号在阿尔茨海默病早期发生改变，但由于大脑老化，也会向激活状态倾斜。有强有力的遗传证据表明，先天免疫在阿尔茨海默病中起着重要作用。在补体级联中起作用的两个基因座CR1和CLU的变异与AD有显著的遗传关联，TREM2中罕见的编码变异也会增加AD的风险。在AD小鼠模型中进行的大量实验研究表明，操纵先天免疫通路可以对蛋白质停滞、认知和神经变性产生积极或消极的影响。至少当评估A病理作为终点时，一些先天免疫系统操作的有益效果是强大的。我们建议在阿尔茨海默病的先天免疫信号级联中确定治疗靶点，这些靶点可以安全地操纵以提供阿尔茨海默病的疾病修饰。然而，由于CNS内先天免疫信号的复杂性和我们对其知识的差距，需要一种集成多种类型数据的系统级方法来实现这一目标。事实上，任何先天免疫疗法的发展都需要精细调整和广泛验证，以便进一步发展为潜在的阿尔茨海默病治疗。我们将使用多方面的系统水平方法来确定先天免疫信号通路中的靶标，这些靶标可以安全地提供AD的疾病修饰作用。来自人类和小鼠模型的全面的转录组学、遗传和病理数据将以新的方式生成、整合和分析。这些综合数据将用于指导APP和tau小鼠模型以及非转基因小鼠中关键先天免疫靶点的多项临床前靶点验证研究。这些研究将极大地加速阿尔茨海默病中疾病修饰的先天免疫调节策略的识别和验证，并将为先天免疫激活状态的这些不同操作如何改变正常行为（重点是认知）提供重要见解。

DESCRIPTION (provided by applicant): An invariant feature of the pathological cascade in Alzheimer's diseases (AD) is a reactive gliosis, reflecting an underlying alteration in the innate immune activation state within the brain. Innate immune signaling is altered early in AD, but is also skewed towards an activated state as a consequence of brain aging. There is strong genetic evidence that innate immunity has a significant role in AD. Variants in two genetic loci that play roles in the complement cascade, CR1 and CLU, show significant genetic associations with AD, and rare coding variants in TREM2 also confer substantial risk for AD. Numerous experimental studies in AD mouse models show that manipulating innate immune pathways can have positive or negative effects on proteostasis, cognition and neurodegeneration. At least when assessing A� pathology as an endpoint, the beneficial effects of some innate immune system manipulations are robust. We propose to identify therapeutic targets within the innate immune signaling cascade in AD that could be safely manipulated to provide disease modification in AD. However, because of the complexity of, and the gaps in our knowledge regarding, innate immune signaling within the CNS, a systems level approach that integrates multiple types of data will be required to achieve this goal. Indeed, development of any innate immune therapy will need to be finely tuned and extensively validated in order to be further developed as a potential AD therapy. We will use a multifaceted systems level approach to identify targets within innate immune signaling pathways that can safely provide disease modifying effects in AD. Comprehensive, transcriptomic, genetic and pathological data from both humans and mouse models will be generated, integrated and analyzed in novel ways. This integrated data will then be used to guide multiple preclinical target validation studies of key innate immune targets in both APP and tau mouse models as well as non-transgenic mice. These studies will dramatically accelerate the identification and validation of disease modifying innate immune modulatory strategies in AD and will provide important insights into how these various manipulations of innate immune activation states alter normal behaviors with an emphasis on cognition.