Inflammasome activiation in Alzheimer´s disease

点击翻译按钮获取中文摘要

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.