Bradykinin-induced amyloid precursor protein secretion: a protein kinase C-independent mechanism that is not altered in fibroblasts from patients with sporadic Alzheimer's disease.
We treated human skin fibroblasts with bradykinin (BK) and observed a concentration-dependent increase in the release of soluble amyloid precursor protein (sAPP). The estimated EC50 for the observed effect is 2.8 nM, which is of the same order of magnitude as the reported Kd of BK binding in human skin fibroblasts. The effect of BK on sAPP secretion appears to be dependent on interaction of the ligand with the B2 type of BK receptors but independent of activation of protein kinase C. We also show that sAPP release after BK treatment in fibroblasts from patients with sporadic Alzheimer's disease is not different from control cells and is paralleled by equivalent levels of inositol trisphosphate production. A discussion of the differences from previously published work focuses on the possible divergent alterations in transduction systems in fibroblasts from patients with familial and sporadic Alzheimer's disease. Our results are the first example of receptor-mediated sAPP release in human skin fibroblasts and the first demonstration of the co-existence of protein kinase C-dependent and -independent mechanisms in these cells.
Racchi
M
M
Laboratory of Cellular and Molecular Neurobiology, Alzheimer's Disease Unit, I.R.C.C.S. San Giovanni di Dio, Sacred Heart Hospital-FBF, Brescia, Italy.
Ianna
P
P
Binetti
G
G
Trabucchi
M
M
Govoni
S
S
D000328:Adult; D000368:Aged; D000544:Alzheimer Disease / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis* / Q000378:metabolism; D001920:Bradykinin / Q000031:analogs & derivatives / Q000494:pharmacology*; D065168:Bradykinin Receptor Antagonists; D002478:Cells, Cultured; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D007700:Kinetics; D008297:Male; D011493:Protein Kinase C / Q000378:metabolism*; D043782:Receptor, Bradykinin B2; D018002:Receptors, Bradykinin / Q000502:physiology; D012016:Reference Values; D012867:Skin / Q000187:drug effects / Q000378:metabolism*
D016564:Amyloid beta-Protein Precursor; D065168:Bradykinin Receptor Antagonists; D043782:Receptor, Bradykinin B2; D018002:Receptors, Bradykinin; C065679:icatibant; D015544:Inositol 1,4,5-Trisphosphate; D011493:Protein Kinase C; D001920:Bradykinin