The major defining pathological hallmark of Alzheimer’s disease (AD) is the accumulation of amyloid protein (A), a small peptide derived from - and -secretase cleavages of the amyloid precursor protein (APP). Recent studies have shown that - and -secretase activities of BACE1 and presenilin, respectively, are concentrated in intracellular lipid raft microdomains. However, the manner in which APP normally traffics to lipid rafts is unknown. In this study, using transient transfection and immuno-precipitation assays, we show that the cytoplasmic domain of low-density lipoprotein receptor-related protein (LRP) interacts with APP and increases A secretion and APP -CTF (C-terminal fragment) generation by promoting BACE1-APP interaction. We also employed discontinuous sucrose density gradient ultracentrifugation to show that the LRP cytoplasmic domain-mediated effect was accompanied by greatly increased localization of APP and BACE1 to lipid raft membranes, where - and -secretase activities are highly enriched. Moreover, we provide evidence that endogenous LRP is required for the normal delivery of APP to lipid rafts and A generation primarily in the endocytic but not secretory pathway. These results may provide novel insights to block A generation by targeting LRP-mediated delivery of APP to raft microdomains. --Yoon, I.-S., Chen, E., Busse, T., Repetto, E., Lakshmana, M. K., Koo, E. H., Kang, D. E. Low-density lipoprotein receptor-related protein promotes amyloid precursor protein trafficking to lipid rafts in the endocytic pathway.