Letter | Published:

The prolyl isomerase Pin1 regulates amyloid precursor protein processing and amyloid-β production

Nature volume 440, pages 528534 (23 March 2006) | Download Citation

Subjects

  • A Corrigendum to this article was published on 15 March 2007

Abstract

Neuropathological hallmarks of Alzheimer's disease are neurofibrillary tangles composed of tau and neuritic plaques comprising amyloid-β peptides (Aβ) derived from amyloid precursor protein (APP), but their exact relationship remains elusive1,2,3. Phosphorylation of tau and APP on certain serine or threonine residues preceding proline affects tangle formation and Aβ production in vitro3,4,5. Phosphorylated Ser/Thr-Pro motifs in peptides can exist in cis or trans conformations, the conversion of which is catalysed by the Pin1 prolyl isomerase6,7. Pin1 has been proposed to regulate protein function by accelerating conformational changes7,8,9,10, but such activity has never been visualized and the biological and pathological significance of Pin1 substrate conformations is unknown7. Notably, Pin1 is downregulated and/or inhibited by oxidation in Alzheimer's disease neurons, Pin1 knockout causes tauopathy and neurodegeneration8,9,11,12, and Pin1 promoter polymorphisms appear to associate with reduced Pin1 levels and increased risk for late-onset Alzheimer's disease13,14. However, the role of Pin1 in APP processing and Aβ production is unknown. Here we show that Pin1 has profound effects on APP processing and Aβ production. We find that Pin1 binds to the phosphorylated Thr 668-Pro motif in APP and accelerates its isomerization by over 1,000-fold, regulating the APP intracellular domain between two conformations, as visualized by NMR. Whereas Pin1 overexpression reduces Aβ secretion from cell cultures, knockout of Pin1 increases its secretion. Pin1 knockout alone or in combination with overexpression of mutant APP in mice increases amyloidogenic APP processing and selectively elevates insoluble Aβ42 (a major toxic species) in brains in an age-dependent manner, with Aβ42 being prominently localized to multivesicular bodies of neurons, as shown in Alzheimer's disease before plaque pathology15. Thus, Pin1-catalysed prolyl isomerization is a novel mechanism to regulate APP processing and Aβ production, and its deregulation may link both tangle and plaque pathologies. These findings provide new insight into the pathogenesis and treatment of Alzheimer's disease.

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Acknowledgements

We thank D. Selkoe for advice, B. Arosio and G. Annoni for sharing results on Pin1 genetic analysis in Alzheimer's disease before publication, D. Selkoe, D. Schenk, P. Seubert, D. Goldgaber, E. Koo, J. Wang and H. Xu for reagents, and J. Sears, H. Yi and M. Wotkowicz for technical assistance. J.L. is a Fellow of the Human Frontier Research Program; G.W. is a NIH Mentored Clinician Scientist. This study was supported by a Taiwan NSC grant to P.J.L., an NSF grant to L.K.N. and NIH grants to X.L., W.X., X.Z.Z. and K.P.L.

Author information

Author notes

    • Anyang Sun

    †Present address: Institute of Neurobiology, Fudan University, Shanghai 200433, China

    • Lucia Pastorino
    • , Anyang Sun
    •  & Pei-Jung Lu

    *These authors contributed equally to this work

Affiliations

  1. Cancer Biology Program, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA

    • Lucia Pastorino
    • , Anyang Sun
    • , Xiao Zhen Zhou
    • , Martin Balastik
    • , Greg Finn
    • , Gerburg Wulf
    • , Jormay Lim
    •  & Kun Ping Lu
  2. Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung 804, Taiwan, China

    • Pei-Jung Lu
  3. Department of Human Genetics, Emory University, Atlanta, Georgia 30322, USA

    • Shi-Hua Li
    •  & Xiaojiang Li
  4. Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA

    • Weiming Xia
  5. Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York 14853, USA

    • Linda K. Nicholson

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Competing interests

Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests.

Corresponding author

Correspondence to Kun Ping Lu.

Supplementary information

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    Supplementary Notes

    This file contains the Supplementary Methods, Supplementary Figures 1–9 and additional references.

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    This file contains a list of genes or proteins used in this study.

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DOI

https://doi.org/10.1038/nature04543

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