The nuclear cofactor Receptor interacting protein-140 (RIP140) regulates the expression of genes involved in Aβ generation

Abstract The Receptor Interacting Protein 140 (RIP140) is a cofactor for several nuclear receptors and has been involved in the regulation of metabolic and inflammatory genes. We hypothesize that RIP140 may also affect Aβ generation because it modulates the activity of transcription factors previously implicated in APP processing, such as PPARγ. We found that the levels of RIP140 are reduced in AD post-mortem brains compared with healthy controls. In addition, in situ hybridization experiments revealed that RIP140 expression is enriched in the same brain areas involved in AD pathology, such as cortex and hippocampus. Furthermore, we provide evidence using cell lines and genetically modified mice that RIP140 is able to modulate the transcription of certain genes involved in AD pathology, such as BACE1 and GSK3. Consequently, we found that RIP140 overexpression reduced the generation of Aβ in a neuroblastoma cell line by decreasing the transcription of BACE1 via a PPARγ-dependent mechanism. The results of this study therefore provide molecular insights into common signalling pathways linking metabolic disease with AD.