ALZHEIMERS-SPECIFIC EFFECTS OF SOLUBLE BETA-AMYLOID ON PROTEIN-KINASE-C-ALPHA AND PROTEIN-KINASE-C-GAMMA DEGRADATION IN HUMAN FIBROBLASTS

Alzheimer's disease (AD) is a multifactorial disease in which beta-amy loid peptide (beta AP) plays a critical role. We report here that the soluble fraction 1-40 of beta AP differentially degrades protein kinas e C-alpha and -gamma (PKC alpha and PKC gamma) isoenzymes in normal (a ge-matched controls, AC) and AD fibroblasts most likely through proteo lytic cascades. Treatment with nanomolar concentrations of beta AP(1-4 0) induced a 75% decrease in PKC alpha, but not PKC gamma, immunoreact ivity in AC fibroblasts, In the AD fibroblasts, a 70% reduction of the PKC gamma, but not PKC alpha, immunoreactivity was observed after bet a AP treatment. Preincubation of AC or AD fibroblasts with 50 mu M lac tacystine, a selective proteasome inhibitor, prevented beta-AP(1-40)-m ediated degradation of PKC alpha in the AC cells, and PKC gamma in the AD fibroblasts. The effects of beta AP(1-40) on PKC alpha in AC fibro blasts were prevented by inhibition of protein synthesis and reversed by PKC activation. A 3-hr treatment with 100 nM phorbol 12-myristate 1 3-acetate restored the PKC alpha signal in treated AC cells but it did not reverse the effects of beta AP(1-40) on PKC gamma in the AD fibro blasts. Pretreatment with the protein synthesis inhibitor, cycloheximi de (CHX. 100 mu M), inhibited the effects of beta AP(1-40) on PKC alph a and blocked the rescue effect of phorbol 12-myristate 13-acetate in AC fibroblasts but did not modify PKC gamma immunoreactivity in AD cel ls, These results suggest that beta AP(1-40) differentially affects PK C regulation in AC and AD cells via proteolytic degradation and that P KC activation exerts a protective role via de novo protein synthesis i n normal but not AD cells.