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The Journal of Neuroscience, April 28, 2004, 24(17):4259-4265; doi:10.1523/JNEUROSCI.5451-03.2004

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Neurobiology of Disease
FE65 Constitutes the Functional Link between the Low-Density Lipoprotein Receptor-Related Protein and the Amyloid Precursor Protein

Claus U. Pietrzik,^1,2 Il-Sang Yoon,¹ Sebastian Jaeger,² Tracy Busse,¹ Sascha Weggen,¹ and Edward H. Koo¹

¹Department of Neurosciences, University of California, San Diego, La Jolla, California 92093, and ²Institute for Pathobiochemistry, University of Mainz, 55099 Mainz, Germany

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 -amyloid precursor protein (APP) processing and affects amyloid -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.

Key words: alzheimer; amyloid precursor protein; APP; lipoprotein; low-density lipoprotein receptor-related protein; LRP; FE65; trafficking

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Received Dec 11, 2003; revised March 16, 2004; accepted March 16, 2004.

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