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Vasopressin and Bradykinin Regulate Secretory Processing of the Amyloid Protein Precursor of Alzheimer's Disease

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Abstract

The amyloid protein precursor (APP) can be processed via several alternative processing pathways, α-secretase processing by cleavage within the amyloid β-peptide domain of APP is highly regulated by several external and internal signals including G protein-coupled receptors, protein kinase C and phospholipase A2. In order to demonstrate that G protein-coupled neuropeptide receptors for bradykinin and vasopressin can increase α-secretase processing of APP, we stimulated endogenously expressed bradykinin or vasopressin receptors in cell culture with the neuropeptides and measured the secreted ectodomain (APPs) in the conditioned media. Both bradykinin and vasopressin rapidly increased phosphatidylinositol (PI) turnover in PC-12 and in NRK-49F cells, indicating that these cell lines constitutively expressed functional PI-linked receptors for these neuropeptides. Both bradykinin and vasopressin readily stimulated APPs secretion. Increased APPs secretion was concentration-dependent and saturable, and it was blocked by receptor antagonists indicating specific receptor interaction of the peptides. The bradykinin-induced increase in APPs secretion in PC-12 cells was mediated by protein kinase C (PKC), whereas vasopressin receptors in NRK-49F cells were coupled to APP processing by PKC-independent signalling pathways. Our data show that neuropeptides can modulate APP processing in cell culture. In as much as increased α-secretase processing is associated with decreased formation of Aβ1–40, a major constituent of amyloid plaques, our findings suggest a possible role for modulating neuropeptide receptors as a strategy for altering amyloid metabolism in Alzheimer's disease brain.

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Authors and Affiliations

  1. Center for Molecular Neurobiology, University of Hamburg, Germany

    Roger M. Nitsch

  2. Department of Brain and Cognitive Sciences, USA

    Cindy Kim

  3. Massachusetts Institute of Technology, Cambridge, MA, and Department of Neurology, Massachusetts General Hospital, Boston, MA

    John H. Growdon

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  1. Roger M. Nitsch
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  2. Cindy Kim
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  3. John H. Growdon
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Nitsch, R.M., Kim, C. & Growdon, J.H. Vasopressin and Bradykinin Regulate Secretory Processing of the Amyloid Protein Precursor of Alzheimer's Disease. Neurochem Res 23, 807–814 (1998). https://doi.org/10.1023/A:1022423813362

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