Low density lipoprotein-related protein (LRP) is a transmembrane receptor, localized mainly in hepatocytes, fibroblasts, and neurons. It is implicated in diverse biological processes both as an endocytic receptor and as a signaling molecule. Recent reports show that LRP undergoes sequential proteolytic cleavage in the ectodomain and transmembrane domain. The latter cleavage, mediated by the Alzheimer-related gamma-secretase activity that also cleaves amyloid precursor protein (APP) and Notch, results in the release of the LRP cytoplasmic domain (LRPICD) fragment. This relatively small cytoplasmic fragment has several motifs by which LRP interacts with various intracellular adaptor and scaffold proteins. However, the function of this fragment is largely unknown. Here we show that the LRPICD is translocated to the nucleus, where it colocalizes in the nucleus with a transcription modulator, Tip60, which is known to interact with Fe65 and with the APP-derived intracellular domain. LRPICD dramatically inhibits APP-derived intracellular domain/Fe65 transactivation mediated by Tip60. LRPICD has a close interaction with Tip60 in the nucleus, as shown by a fluorescence resonance energy transfer assay. These observations suggest that LRPICD has a novel signaling function, negatively impacting transcriptional activity of the APP, Fe65, and Tip60 complex in the nucleus, and shed new light on the function of LRP in transcriptional modulation.