Soluble β-amyloid Precursor Protein Alpha binds to p75 neurotrophin receptor to promote neurite outgrowth

Noriko Hasebe; Yuki Fujita; Masaki Ueno; Kazuhiro Yoshimura; Yuji Fujino; Toshihide Yamashita

doi:10.1371/journal.pone.0082321

Soluble β-amyloid Precursor Protein Alpha binds to p75 neurotrophin receptor to promote neurite outgrowth

PLoS One. 2013 Dec 16;8(12):e82321. doi: 10.1371/journal.pone.0082321. eCollection 2013.

Authors

Noriko Hasebe¹, Yuki Fujita², Masaki Ueno³, Kazuhiro Yoshimura⁴, Yuji Fujino⁵, Toshihide Yamashita²

Affiliations

¹ Department of Molecular Neuroscience, Graduate School of Medicine, Osaka University, Osaka, Japan ; Department of Anesthesiology and Critical Care Medicine, Graduate School of Medicine, Osaka University, Osaka, Japan ; Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), Tokyo, Japan.
² Department of Molecular Neuroscience, Graduate School of Medicine, Osaka University, Osaka, Japan ; Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), Tokyo, Japan.
³ Department of Molecular Neuroscience, Graduate School of Medicine, Osaka University, Osaka, Japan ; Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), Tokyo, Japan ; Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America.
⁴ Department of Molecular Neuroscience, Graduate School of Medicine, Osaka University, Osaka, Japan ; Department of Neurosurgery, Graduate School of Medicine, Osaka University, Osaka, Japan.
⁵ Department of Anesthesiology and Critical Care Medicine, Graduate School of Medicine, Osaka University, Osaka, Japan.

Abstract

Background: The cleavage of β-amyloid precursor protein (APP) generates multiple proteins: Soluble β-amyloid Precursor Protein Alpha (sAPPα), sAPPβ, and amyloid β (Aβ). Previous studies have shown that sAPPα and sAPPβ possess neurotrophic properties, whereas Aβ is neurotoxic. However, the underlying mechanism of the opposing effects of APP fragments remains poorly understood. In this study, we have investigated the mechanism of sAPPα-mediated neurotrophic effects. sAPPα and sAPPβ interact with p75 neurotrophin receptor (p75(NTR)), and sAPPα promotes neurite outgrowth.

Methods and findings: First, we investigated whether APP fragments interact with p75(NTR), because full-length APP and Aβ have been shown to interact with p75(NTR) in vitro. Both sAPPα and sAPPβ were co-immunoprecipitated with p75(NTR) and co-localized with p75(NTR) on COS-7 cells. The binding affinity of sAPPα and sAPPβ for p75(NTR) was confirmed by enzyme-linked immunosorbent assay (ELISA). Next, we investigated the effect of sAPPα on neurite outgrowth in mouse cortical neurons. Neurite outgrowth was promoted by sAPPα, but sAPPα was uneffective in a knockdown of p75(NTR).

Conclusion: We conclude that p75(NTR) is the receptor for sAPPα to mediate neurotrophic effects.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amyloid beta-Protein Precursor / metabolism*
Animals
COS Cells
Cerebral Cortex / metabolism*
Chlorocebus aethiops
Mice
Neurites / metabolism*
Neurons / metabolism*
Receptor, Nerve Growth Factor / metabolism*

Substances

Amyloid beta-Protein Precursor
Receptor, Nerve Growth Factor

Grants and funding

This work was supported by a Grant-in-Aid for Scientific Research (S) from JSPS (25221309) to T.Y. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.