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Modulation of BAG3 Expression and Proteasomal Activity by sAPPα Does Not Require Membrane-Tethered Holo-APP

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Abstract

Maintenance of intracellular proteostasis is essential for neuronal function, and emerging data support the view that disturbed proteostasis plays an important role in brain aging and the pathogenesis of age-related neurodegenerative disorders such as Alzheimer’s disease (AD). sAPPalpha (sAPPα), the extracellularly secreted N-terminal alpha secretase cleavage product of the amyloid precursor protein (APP), has an established function in neuroprotection. Recently, we provided evidence that membrane-bound holo-APP functionally cooperates with sAPPα to mediate neuroprotection via activation of the Akt survival signaling pathway and sAPPα directly affects proteostasis. Here, we demonstrate that in addition to its anti-apoptotic function, sAPPα has effects on neuronal proteostasis under conditions of proteasomal stress. In particular, recombinant sAPPα significantly suppressed MG132-triggered expression of the co-chaperone BAG3 and aggresome formation, and it partially rescued proteasomal activity in a dose-dependent manner in SH-SY5Y neuroblastoma cells. In analogy, sAPPα was able to inhibit MG132-induced BAG3 expression in primary hippocampal neurons. Strikingly, these sAPPα-induced changes were unaltered in APP-depleted SH-SY5Y cells and APP-deficient neurons, demonstrating that holo-APP is not required for this particular function of sAPPα. Importantly, recombinant sAPPbeta (sAPPβ) failed to modulate BAG3 expression and proteostasis in APP-proficient wild-type (wt) cells, indicating that these biological effects are highly selective for sAPPα. In conclusion, we demonstrate that modulation of proteostasis is a distinct biological function of sAPPα and does not require surface-bound holo-APP. Our data shed new light on the physiological functions of APP and the interplay between APP processing and proteostasis during brain aging.

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Acknowledgments

This study was supported by the Deutsche Forschungsgemeinschaft (DFG, grants KO 1898/6-1 and 10-1 to DK; BE 1475/8-1 to CB; KI 819/5-1 and 819/6-1 to SK; MU 1457/8-1 and 1457/9-1 to UCM; and DFG/Collaborative Research Center 1080 to CB). We thank Gabriele Köpf for excellent technical assistance.

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Authors and Affiliations

  1. Experimental Neurosurgery, Frankfurt University Hospital, Frankfurt, Germany

    Arpita Kundu, Nelli Milosch, Patrick Antonietti, Andreas Zymny & Donat Kögel

  2. Division of Human Biology and Human Genetics, Technical University of Kaiserslautern, Kaiserslautern, Germany

    Frederik Baumkötter & Stefan Kins

  3. Department of Bioinformatics and Functional Genomics, Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, Heidelberg, Germany

    Ulrike C. Müller

  4. Institute of Pathobiochemistry, University Medical Center, Mainz University, Mainz, Germany

    Parvana Hajieva & Christian Behl

  5. Experimental Neurosurgery, Goethe University Hospital, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany

    Donat Kögel

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  1. Arpita Kundu
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  2. Nelli Milosch
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  9. Christian Behl
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Correspondence to Donat Kögel.

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Kundu, A., Milosch, N., Antonietti, P. et al. Modulation of BAG3 Expression and Proteasomal Activity by sAPPα Does Not Require Membrane-Tethered Holo-APP. Mol Neurobiol 53, 5985–5994 (2016). https://doi.org/10.1007/s12035-015-9501-y

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  • DOI: https://doi.org/10.1007/s12035-015-9501-y

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