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APP intracellular domain–WAVE1 pathway reduces amyloid-β production

Nature Medicine volume 21, pages 1054–1059 (2015)Cite this article

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Abstract

An increase in amyloid-β (Aβ) production is a major pathogenic mechanism associated with Alzheimer's disease (AD)1,2, but little is known about possible homeostatic control of the amyloidogenic pathway. Here we report that the amyloid precursor protein (APP) intracellular domain (AICD) downregulates Wiskott-Aldrich syndrome protein (WASP)-family verprolin homologous protein 1 (WAVE1 or WASF1) as part of a negative feedback mechanism to limit Aβ production. The AICD binds to the Wasf1 promoter, negatively regulates its transcription and downregulates Wasf1 mRNA and protein expression in Neuro 2a (N2a) cells. WAVE1 interacts and colocalizes with APP in the Golgi apparatus. Experimentally reducing WAVE1 in N2a cells decreased the budding of APP-containing vesicles and reduced cell-surface APP, thereby reducing the production of Aβ. WAVE1 downregulation was observed in mouse models of AD. Reduction of Wasf1 gene expression dramatically reduced Aβ levels and restored memory deficits in a mouse model of AD. A decrease in amounts of WASF1 mRNA was also observed in human AD brains, suggesting clinical relevance of the negative feedback circuit involved in homeostatic regulation of Aβ production.

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Figure 1: Downregulation of WAVE1 expression by overexpression of APP or AICD.
Figure 2: A reduction in WAVE1 expression leads to reduced levels of Aβ.
Figure 3: WAVE1 facilitates budding of APP-containing vesicles from the Golgi apparatus.
Figure 4: Behavioral consequences and clinical relevance of WAVE1 downregulation and a model for negative feedback regulation of Aβ production.

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Acknowledgements

This work was supported by the US National Institutes of Health (grants AG009464 (to P.G.) and AG047270 (to A.C.N.)), the Fisher Center for Alzheimer's Research Foundation (to P.G.) and the US Department of Defense–USAMRAA (grants W81XWH-09-1-0392 (to Y.K.) and W81XWH-09-1-0402 (to P.G.)). J.-H.A. was supported by the Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Science, ICT & Future Planning (2010-0027945). We thank W. Luo for protocols for metabolic pulse labeling and chase and organelle fractionation; W.J. Netzer (The Rockefeller University, New York, New York, USA) for sAPPβ antibody and mNotchΔE plasmid; D. Cai for the budding-assay protocol; and S.S. Sisodia for the pCB6-APP695wt and pCB6-APP695swe plasmids. We also thank A. Schaeffer, P. Kurup, P. Lombroso, D. Tampellini, G. Gouras and R. Moir for discussion or sharing of materials. We acknowledge R. Norinsky and The Rockefeller University Transgenics Services Laboratory for their excellent in vitro fertilization services, Z. Dong for research assistance and E. Griggs for graphics.

Author information

Authors and Affiliations

  1. Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, New York, USA

    Ilaria Ceglia, Jodi Gresack, Victor Bustos, Xiaozhu Zhang, Grant Martin, Angus C Nairn, Paul Greengard & Yong Kim

  2. The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, New York, USA

    Christiane Reitz

  3. The Gertrude H. Sergievsky Center, Columbia University, New York, New York, USA

    Christiane Reitz

  4. Department of Neurology, Columbia University, New York, New York, USA

    Christiane Reitz

  5. Department of Epidemiology, Columbia University, New York, New York, USA

    Christiane Reitz

  6. Department of Biochemistry, Ewha Womans University, Seoul, South Korea

    Jung-Hyuck Ahn

  7. Tissue Injury Defense Research Center, School of Medicine, Ewha Womans University, Seoul, South Korea

    Jung-Hyuck Ahn

  8. Laboratory of Cellular Biophysics, The Rockefeller University, New York, New York, USA

    Marina Bleck & Sanford M Simon

  9. Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut, USA

    Angus C Nairn

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Contributions

Y.K., I.C., A.C.N. and P.G. designed experiments and wrote the manuscript. I.C. and Y.K. analyzed WAVE1 expression in N2a cells and mice. I.C. carried out ChIP and immunohistochemistry assays of WAVE1. J.-H.A. constructed plasmids including AICD-3×Flag and performed real-time PCR. I.C. and J.-H.A. performed promoter-luciferase assays. V.B. and I.C. analyzed AICD and Aβ expression. Y.K. and I.C. performed metabolic pulse labeling and chase experiments and in vitro budding assays. C.R. analyzed WAVE1 expression in human samples. X.Z. prepared mice. J.G. performed behavioral experiments. G.M., M.B., S.M.S. and Y.K. performed immunocytochemical experiments and data analysis.

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Correspondence to Yong Kim.

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Ceglia, I., Reitz, C., Gresack, J. et al. APP intracellular domain–WAVE1 pathway reduces amyloid-β production. Nat Med 21, 1054–1059 (2015). https://doi.org/10.1038/nm.3924

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