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 beta-amyloid precursor protein (APP) interacts with LRP and that this association may impact the production of amyloid beta-protein (Abeta). 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, Abeta 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 Abeta production, through interactions of the cytosolic domains.
Pietrzik
Claus U
CU
Department of Neurosciences, University of California, San Diego, La Jolla 92093, USA.
Busse
Tracy
T
Merriam
David E
DE
Weggen
Sascha
S
Koo
Edward H
EH
D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D003593:Cytoplasm / Q000378:metabolism*; D018076:DNA, Complementary; D004797:Enzyme-Linked Immunosorbent Assay; D005347:Fibroblasts / Q000378:metabolism; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D051379:Mice; D011233:Precipitin Tests; D011499:Protein Processing, Post-Translational
D016564:Amyloid beta-Protein Precursor; D018076:DNA, Complementary; D026503:Low Density Lipoprotein Receptor-Related Protein-1