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Reticulon family members modulate BACE1 activity and amyloid-β peptide generation

Nature Medicine volume 10, pages 959965 (2004) | Download Citation

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Abstract

Inhibiting the activity of the β-amyloid converting enzyme 1 (BACE1) or reducing levels of BACE1 in vivo decreases the production of amyloid-β. The reticulon family of proteins has four members, RTN1, RTN2, RTN3 and RTN4 (also known as Nogo), the last of which is well known for its role in inhibiting neuritic outgrowth after injury. Here we show that reticulon family members are binding partners of BACE1. In brain, BACE1 mainly colocalizes with RTN3 in neurons, whereas RTN4 is more enriched in oligodendrocytes. An increase in the expression of any reticulon protein substantially reduces the production of Aβ. Conversely, lowering the expression of RTN3 by RNA interference increases the secretion of Aβ, suggesting that reticulon proteins are negative modulators of BACE1 in cells. Our data support a mechanism by which reticulon proteins block access of BACE1 to amyloid precursor protein and reduce the cleavage of this protein. Thus, changes in the expression of reticulon proteins in the human brain are likely to affect cellular amyloid-β and the formation of amyloid plaques.

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Acknowledgements

We thank W.R. Mathews and E. Lund for assistance in sample sequencing by MALDI-TOF mass spectroscopy; J. Blaesdale, G. Gill and Q. Shi for discussions; G. Kidd for help with confocal microscopy; and B. Trapp for support and discussion.

Author information

Affiliations

  1. Department of Neurosciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.

    • Wanxia He
    • , Xiang-You Hu
    • , Ansi Chang
    •  & Riqiang Yan
  2. Cell & Molecular Biology, Pharmacia Corporation, Kalamazoo, Michigan 49007, USA.

    • Yifeng Lu
    • , Isam Qahwash
    •  & Riqiang Yan

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The authors declare no competing financial interests.

Corresponding author

Correspondence to Riqiang Yan.

Supplementary information

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  1. 1.

    Supplementary Fig. 1

    Tissue distribution of RTN3/Nogo proteins

  2. 2.

    Supplementary Fig. 2

    Transfected RTN3 does not affect Aβ ratios.

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DOI

https://doi.org/10.1038/nm1088