Inflammasome activiation in Alzheimer´s disease

在阿尔茨海默病(AD)患者的大脑中，被激活的小胶质细胞包围的蛋白质聚集体(老年斑)的沉积是典型的组织病理学特征。老年斑出现在灰质，主要由细胞外淀粉样β蛋白(A？)组成。我们在体外发现，聚集形式的Aü导致胞质受体复合体激活，称为NLRP3炎症体。炎症性小体控制炎症caspase-1的活性，而炎症caspase-1是处理细胞因子家族成员的前体所必需的。值得注意的是，NLRP3炎症体的活性对于神经毒性因子的分泌以及趋化因子的分泌都是至关重要的。在这里，我们建议通过研究缺乏NLRP3炎症体途径关键成分的AD小鼠模型来测试NLRP3炎症体识别聚集A？的体内相关性。此外，我们将建立一个治疗模型，允许测试ANFI-LL-1治疗对AD发展的影响。这些小鼠将被分析阿尔茨海默病的临床症状和大脑的组织病理学变化。这些研究将加深我们对炎性小体和IL-1细胞因子在AD病理生理学中的作用的理解。

In brains of Alzheimer's disease (AD) patients, deposits of proteinaceous aggregates (senile plaques) surrounded by activated microglia cells are characteristic histopathological features. Senile plaques appear in the grey matter and consist mainly of extracellular Amyloid beta peptide (Aß). We found in vitro that the aggregated forms of Aß led to the activation of a cytosolic receptor complex, termed the NLRP3 inflammasome. Inflamma-somes control the activity of the inflammatory caspase-1, which is required to process the precursors of lL-1 ß cytokine family members. Notably, the activity of the NLRP3 inflammasome was critical for the secretion of neuro-toxic factors as well as for chemokines. Here, we propose to test the in vivo relevance of the recognition of aggregated Aß by the NLRP3 inflammasome by studying a murine model of AD in the absence of critical components of the NLRP3 inflammasome pathway. In addition, we will establish a treatment model that allows testing the effect of anfi-lL-1 treatment on the development of AD. These mice will be analyzed for clinical signs of AD and histopatho-logical changes in the brain. These studies will enhance our understanding of the roles of inflammasomes and lL-1 cytokines in the pathophysiology of AD.