The cytoplasmic domain of the LDL receptor-related protein regulates multiple steps in APP processing

The low-density lipoprotein receptor-related protein (LRP) has recently been implicated in numerous intracellular signaling functions, as well as in Alzheimer’s disease pathogenesis. Studies have shown that the β-amyloid precursor protein (APP) interacts with LRP and that this association may impact the production of amyloid β-protein (Aβ). In this report, we provide evidence that LRP regulates trafficking of intracellular proteins independently of its lipoprotein receptor functions. We show that in the absence of LRP, Aβ production, APP secretion, APP internalization, turnover of full-length APP and stability of APP C-terminal fragments are affected. Importantly, these changes are not APP isoform dependent. Using deletion constructs, the critical region in LRP that modulates APP processing was mapped to a seven peptide domain around the second NPXY domain (residues 4504–4510). Therefore, we propose a model by which LRP functionally modulates APP processing, including those steps critical for Aβ production, through interactions of the cytosolic domains.