The nuclear cofactor receptor interacting protein-140 (RIP140) regulates the expression of genes involved in Aβ generation.
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 amyloid precursor protein (APP) processing, such as peroxisome proliferator-activated receptor-γ (PPARγ). We found that the levels of RIP140 are reduced in Alzheimer's disease (AD) postmortem 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 β-APP cleaving enzyme (BACE1) and GSK3. Consequently, we found that RIP140 overexpression reduced the generation of Aβ in a neuroblastoma cell line by decreasing the transcription of β-APP cleaving enzyme via a PPARγ-dependent mechanism. The results of this study therefore provide molecular insights into common signaling pathways linking metabolic disease with AD.
Division of Brain Sciences, Department of Medicine, Imperial College London, London, UK.
Katrin
K
Blondrath
Institute for Reproductive and Developmental Biology, Department of Surgery & Cancer, Imperial College London, London, UK.
Jennifer H
JH
Steel
Division of Brain Sciences, Department of Medicine, Imperial College London, London, UK.
Loukia
L
Katsouri
Division of Brain Sciences, Department of Medicine, Imperial College London, London, UK.
Miriam
M
Ries
Institute for Reproductive and Developmental Biology, Department of Surgery & Cancer, Imperial College London, London, UK.
Malcolm G
MG
Parker
Division of Metabolic and Vascular Health, Warwick Medical School, University of Warwick, Coventry, UK. Electronic address: M.Christian@warwick.ac.uk.
Mark
M
Christian
Division of Brain Sciences, Department of Medicine, Imperial College London, London, UK. Electronic address: m.sastre@imperial.ac.uk.
Magdalena
M
Sastre
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism / Q000502:physiology*; D000544:Alzheimer Disease / Q000235:genetics*; D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D001921:Brain / Q000378:metabolism; D002478:Cells, Cultured; D005260:Female; D015870:Gene Expression / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D038362:Glycogen Synthase Kinase 3; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009687:Nuclear Proteins / Q000378:metabolism / Q000502:physiology*; D000078723:Nuclear Receptor Interacting Protein 1; D047495:PPAR gamma / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic / Q000235:genetics
D048868:Adaptor Proteins, Signal Transducing; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; C000627127:NRIP1 protein, human; D009687:Nuclear Proteins; D000078723:Nuclear Receptor Interacting Protein 1; D047495:PPAR gamma; D038362:Glycogen Synthase Kinase 3; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse
Alzheimer's disease; Aβ; BACE1; GSK3; PPARγ; RIP140