A system approach to targeting innate immunity in AD

描述(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胶质细胞增生，反映了大脑内天然免疫激活状态的潜在变化。先天免疫信号在阿尔茨海默病早期会发生改变，但也会因为大脑老化而偏向激活状态。有强有力的遗传证据表明，先天免疫在阿尔茨海默病中具有重要作用。在补体级联中起作用的两个遗传位点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增加了AD的风险。在AD小鼠模型上的大量实验研究表明，操纵先天免疫途径可以对蛋白平衡、认知和神经退变产生积极或消极的影响。至少在评估A�病理作为终点时，一些先天免疫系统操作的有益影响是强大的。我们建议在AD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AD的疾病修饰。然而，由于CNS中先天免疫信号的复杂性和我们对其了解的空白，需要一种整合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开发都需要进行精细的调整和广泛的验证，才能进一步开发为潜在的AD疗法。我们将使用多方面的系统水平的方法来识别先天免疫信号通路中的靶点，这些信号通路可以安全地在AD中提供疾病修改效果。来自人类和小鼠模型的全面、转录、遗传和病理数据将以新的方式生成、集成和分析。然后，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模型中关键先天免疫靶点的多个临床前靶点验证研究。这些研究将极大地加速疾病的识别和验证，改变AD的先天性免疫调节策略，并将为这些天然免疫激活状态的各种操作如何改变正常行为提供重要的见解，重点是认知。

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.