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Amyloid precursor protein and amyloid β-peptide bind to ATP synthase and regulate its activity at the surface of neural cells

Molecular Psychiatry volume 13, pages 953–969 (2008)Cite this article

Abstract

Amyloid precursor protein (APP) and amyloid β-peptide (Aβ) have been implicated in a variety of physiological and pathological processes underlying nervous system functions. APP shares many features with adhesion molecules in that it is involved in neurite outgrowth, neuronal survival and synaptic plasticity. It is, thus, of interest to identify binding partners of APP that influence its functions. Using biochemical cross-linking techniques we have identified ATP synthase subunit α as a binding partner of the extracellular domain of APP and Aβ. APP and ATP synthase colocalize at the cell surface of cultured hippocampal neurons and astrocytes. ATP synthase subunit α reaches the cell surface via the secretory pathway and is N-glycosylated during this process. Transfection of APP-deficient neuroblastoma cells with APP results in increased surface localization of ATP synthase subunit α. The extracellular domain of APP and Aβ partially inhibit the extracellular generation of ATP by the ATP synthase complex. Interestingly, the binding sequence of APP and Aβ is similar in structure to the ATP synthase–binding sequence of the inhibitor of F1 (IF1), a naturally occurring inhibitor of the ATP synthase complex in mitochondria. In hippocampal slices, Aβ and IF1 similarly impair both short- and long-term potentiation via a mechanism that could be suppressed by blockade of GABAergic transmission. These observations indicate that APP and Aβ regulate extracellular ATP levels in the brain, thus suggesting a novel mechanism in Aβ-mediated Alzheimer's disease pathology.

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Acknowledgements

We thank Frank Plöger and Henrike Neuhoff for preliminary experiments, Fritz Buck for sequencing of protein bands, Matthias Staufenbiel for APP transgenic mice, Gerd Multhaup for the 22C11, WO-2 and 22734 antibodies, Sangram Sisodia for mouse APP 695 cDNA, Saskia Siegel and Galina Dityateva for help with hippocampal cultures and Wiebke Höppner and Sina Müthing for help with the ATPase assay. MS is New Jersey professor for spinal cord research.

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  1. E Lepsverdize and S L Chi: These authors contributed equally to this work.

Authors and Affiliations

  1. Zentrum für Molekulare Neurobiologie, Universität Hamburg, Hamburg, Germany

    C Schmidt, E Lepsverdize, A Dityatev & M Schachner

  2. Department of Pathology, Duke University Medical Center, Durham, NC, USA

    S L Chi & S V Pizzo

  3. Medizinische Hochschule Hannover, Hannover, Germany

    A M Das

  4. Keck Center for Collaborative Neuroscience and Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ, USA

    M Schachner

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Schmidt, C., Lepsverdize, E., Chi, S. et al. Amyloid precursor protein and amyloid β-peptide bind to ATP synthase and regulate its activity at the surface of neural cells. Mol Psychiatry 13, 953–969 (2008). https://doi.org/10.1038/sj.mp.4002077

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