Amyloid precursor protein metabolism in fibroblasts from individuals with one, two or three copies of the amyloid precursor protein (APP) gene

Protein kinase C (PKC)-activated modulation of amyloid precursor protein (A PP) metabolism has been investigated in natural models of altered APP expre ssion due to the presence of one, two or three copies of the APP gene. We s how that levels of APP present in human skin fibroblasts strongly influence the effect of PKC activation of soluble APP (sAPP) release. Thus fibroblas ts derived from a patient with a deletion in chromosome 21 including the AP P locus (Delta 21) had lower levels of both APP mRNA and cell-associated AP P, and showed an exaggerated phorbol-ester-induced sAPP release, when compa red with fibroblasts from control individuals. In contrast, fibroblasts fro m chromosome 21 trisomic Down's syndrome patients failed to show a concentr ation-dependent response to phorbol ester treatment. These results suggest that the levels of APP expression can affect the degree of response to PKC- mediated modulation of the metabolism of this protein.