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Low-Density Lipoprotein Receptor-Related Protein-1 (LRP1) C4408R Mutant Promotes Amyloid Precursor Protein (APP) α-Cleavage in Vitro

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Abstract

Previous studies have demonstrated that the low-density lipoprotein receptor-related protein-1 (LRP1) plays conflicting roles in Alzheimer’s disease (AD) pathogenesis, clearing β-amyloid (Aβ) from the brain while also enhancing APP endocytosis and resultant amyloidogenic processing. We have recently discovered that co-expression of mutant LRP1 C-terminal domain (LRP1-CT C4408R) with Swedish mutant amyloid precursor protein (APPswe) in Chinese hamster ovary (CHO) cells decreases Aβ production, while also increasing sAPPα and APP α-C-terminal fragment (α-CTF), compared with CHO cells expressing APPswe alone. Surprisingly, the location of this mutation on LRP1 corresponded with the α-secretase cleavage site of APP. Further experimentation confirmed that in CHO cells expressing APPswe or wild-type APP (APPwt), co-expression of LRP1-CT C4408R decreases Aβ and increases sAPPα and α-CTF compared with co-expression of wild-type LRP1-CT. In addition, LRP1-CT C4408R enhanced the unglycosylated form of LRP1-CT and reduced APP endocytosis as determined by flow cytometry. This finding identifies a point mutation in LRP1 which slows LRP1-CT-mediated APP endocytosis and amyloidogenic processing, while enhancing APP α-secretase cleavage, thus demonstrating a potential novel target for slowing AD pathogenesis.

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Acknowledgements

This work was supported by the NIH/NIA (R01AG050253, R01AG032432) and the Silver Endowment to J Tan. We would like to thank Dr. David Kang, Dr. Demian Obregon and Dr. Doug Shytle for their helpful discussion and Mr. Yang Gao for his technical support in confocal image analysis. We also appreciated Dr. Stefanie Hahn and Dr. Sascha Weggen for kindly providing us with CHO cells overexpressing human APP bearing the Swedish mutation (APPswe) and human LRP-CT.

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Authors and Affiliations

  1. Rashid Laboratory for Developmental Neurobiology, Silver Child Development Center, Morsani College of Medicine, University of South Florida, Tampa, FL, 33613, USA

    Huayan Hou, Ahsan Habib, Dan Zi, Kathy Tian, Jun Tian, Darrell Sawmiller & Jun Tan

  2. Neuroimmunology Laboratory, Department of Psychiatry and Behavioral Neurosciences, Morsani College of Medicine, University of South Florida, Tampa, FL, 33613, USA

    Brian Giunta

  3. Department of Obstetrics and Gynecology, Guizhou Medical University, Guiyang, 55004, China

    Dan Zi

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  1. Huayan Hou
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Correspondence to Darrell Sawmiller.

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Hou, H., Habib, A., Zi, D. et al. Low-Density Lipoprotein Receptor-Related Protein-1 (LRP1) C4408R Mutant Promotes Amyloid Precursor Protein (APP) α-Cleavage in Vitro. Neuromol Med 19, 300–308 (2017). https://doi.org/10.1007/s12017-017-8446-x

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