Increased processing of amyloid precursor protein (APP) and accumulation of neurotoxic amyloid β-peptide (Aβ) in the brain is central to the pathogenesis of Alzheimers disease (AD). Therefore identification of molecules that regulate Aβ generation is crucial for future therapeutic approaches for AD. We previously demonstrated that RanBP9 regulates Aβ generation in a number of cell lines and primary neuronal cultures, by forming tripartite protein complexes with APP, LRP and BACE1, consequently leading to increased amyloid plaque burden in the brain. RanBP9 is a scaffold protein that exists and functions in multiprotein complexes. In order to identify other proteins that may bind RanBP9 and regulate Aβ levels, we used two-hybrid analysis against a human brain cDNA library, and identified COPS5 as a novel RanBP9-interacting protein. This interaction was confirmed by coimmunoprecipitation experiments in both neuronal and non-neuronal cells and mouse brain. Colocalization of COPS5 and RanBP9 in the same subcellular compartments further supported the interaction of both proteins. Furthermore, like RanBP9, COPS5 robustly increased Aβ generation followed by increased sAPP-β and decreased sAPP-α levels. Most importantly, down regulation of COPS5 by siRNAs reduced Aβ generation, implying that endogenous COPS5 regulates Aβ generation. Finally, COPS5 levels were significantly increased in AD brains and APdE9 transgenic mice and overexpression of COPS5 strongly increased RanBP9 protein levels by increasing its half-life. Taken together these results suggest that COPS5 increases Aβ generation by increasing RanBP9 levels. Thus, COPS5 is a novel RanBP9-binding protein that increases APP processing and Aβ generation by stabilizing RanBP9 protein levels.