Activation of nuclear receptor Peroxisome Proliferator Activated Receptor gamma (PPARγ) has been reported to be protective in Alzheimer's disease (AD) mouse models, by decreasing inflammation and toxic Aβ levels, one of the key features hallmarking the disease. Therefore, the role of PPARγ cofactors will be critical in order to regulate the activity of PPARγ. Our aim was to study the potential role of the PPARγ cofactor Receptor Interacting Protein 140 (RIP140) in AD. Results from our lab showed that RIP140 is reduced in the brain of AD patients. Therefore, we investigated the role of RIP140 on the processing of APP initially in vitro, using a neuroblastoma cell line. Our results suggest that RIP140 over expression reduced Aβ generation and BACE1 protein expression and mRNA levels in a PPARγ activated dependent manner. Conversely, knockdown of RIP140 increased the level of BACE1 protein mRNA and promoter activity. Therefore, RIP140 seems to act as a transcriptional co-activator for PPARγ leading to reductions in BACE1 transcription. Studies performed in animal models, lacking or over expressing RIP140 indicated that many genes involved in the insulin pathway appeared to be modulated by RIP140. In the hippocampus area of mice overexpressing RIP140there was a transcriptional induction of growth factors involved in synaptic plasticity, including growth associated protein 43 (GAP43) and Insulin growth factor2 (IgF2), both being linked to the development of AD but also memory and cognition. In agreement with the in vitro results, the levels of BACE1 were found reduced in the brain of RIP140 transgenic mice, although no alterations on endogenous mouse Aβ levels were detected. Further more, the expression of proteins being involved in the clearance of Aβ plaques, such as ApoE were found increased. RIP140 over expressing mice showed also alteration in genes associated with Tau pathology, such as a reduction of microtubule-associated proteins 1 and 2 and the Tau kinases CDK5 and GSK3. Studies in animals lacking RIP140 showed the opposite effect in most of the above genes and mRNA analysis revealed that BACE1 expression levels were increased in the frontal cortex area, which is in line with our previous results. RIP140 knockout mice showed also increases in the levels of genes involved in Tau pathology, such as GSK3, cdK5 and Mtap2. Interestingly, RIP140 appeared to be involved in the regulation of inflammatory processes in the mouse brain, showing an increase in GFAP staining for astrocytes in RIP140 knockout mice and reductions in the levels of inflammatory cytokines in RIP40 transgenic animals. The results indicate that RIP140 has neuro-protective effects and could serve as therapeutic target for AD, by reducing the levels of BACE1 (the main enzyme involved in Aβ generation), proteins involved in Tau pathology and leading to a decrease of inflammatory processes in the brain.