RIPK1 mediates a disease-associated microglial response in Alzheimer’s disease

作者：Dimitry Ofengeim, Sonia Mazzitelli, Yasushi Ito, Judy Park DeWitt, Lauren Mifflin, Chengyu Zou, Sudeshna Das, Xian Adiconis, Hongbo Chen, Hong Zhu, Michelle A. Kelliher, Joshua Z. Levin, Junying Yuan · 发表于：Proceedings of the National Academy of Sciences · 年份：2017 · DOI：10.1073/pnas.1714175114 · 被引用次数：390 · 研究领域：Neuroinflammation and Neurodegeneration Mechanisms、Alzheimer's disease research and treatments、Atherosclerosis and Cardiovascular Diseases

, a marker for disease-associated microglia (DAM), which encodes an endosomal/lysosomal cathepsin inhibitor named Cystatin F. We present evidence that RIPK1-mediated induction of Cst7 leads to an impairment in the lysosomal pathway. These data suggest that RIPK1 may mediate a critical checkpoint in the transition to the DAM state. Together, our study highlights a non-cell death mechanism by which the activation of RIPK1 mediates the induction of a DAM phenotype, including an inflammatory response and a reduction in phagocytic activity, and connects RIPK1-mediated transcription in microglia to the etiology of AD. Our results support that RIPK1 is an important therapeutic target for the treatment of AD.