FE65 constitutes the functional link between the low-density lipoprotein receptor-related protein and the amyloid precursor protein.
Increasing evidence has implicated the low density lipoprotein receptor-related protein (LRP) and the adaptor protein FE65 in Alzheimer's disease pathogenesis. We have shown previously that LRP mediates beta-amyloid precursor protein (APP) processing and affects amyloid beta-protein and APP secretion and APP-c-terminal fragment generation. Furthermore, LRP mediates APP processing through its intracellular domain. Here, we set out to examine whether this interaction is of direct or indirect nature. Specifically, we asked whether adaptor proteins such as FE65 influence the LRP-mediated effect on APP processing by forming a protein complex. In coimmunoprecipitation experiments, we confirmed the postulated APP-FE65 and the LRP-FE65 interaction. However, we also showed an LRP-FE65-APP trimeric complex using pull-down techniques. Because FE65 alters APP processing, we investigated whether this effect is LRP dependent. Indeed, FE65 was only able to increase APP secretion in the presence of LRP. In the absence of LRP, APP secretion was unchanged compared with the LRP knock-out phenotype. Using RNA short interference techniques against FE65, we demonstrated that a reduction in FE65 protein mimics the LRP knock-out phenotype on APP processing. These results clearly demonstrate that FE65 acts as a functional linker between APP and LRP.
Pietrzik
Claus U
CU
Department of Neurosciences, University of California, San Diego, La Jolla, California 92093, USA. pietrzik@uni-mainz.de
Yoon
Il-Sang
IS
Jaeger
Sebastian
S
Busse
Tracy
T
Weggen
Sascha
S
Koo
Edward H
EH
D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D006224:Cricetinae; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D006801:Humans; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D046911:Macromolecular Substances; D051379:Mice; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011233:Precipitin Tests; D011485:Protein Binding / Q000502:physiology; D011499:Protein Processing, Post-Translational / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000502:physiology; D034622:RNA Interference; D014162:Transfection
C091042:APBB1 protein, human; D016564:Amyloid beta-Protein Precursor; C486243:Apbb1 protein, mouse; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D046911:Macromolecular Substances; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins