Alzheimer's-Specific Effects of Soluble β -amyloid on Protein Kinase C-α and -γ Degradation in Human Fibroblasts
Abstract
Alzheimer's disease (AD) is a multifactorial disease in which β-amyloid peptide (βAP) plays a critical role. We report here that the soluble fraction 1-40 of βAP differentially degrades protein kinase C-α and -γ (PKCα and PKCγ) isoenzymes in normal (age-matched controls, AC) and AD fibroblasts most likely through proteolytic cascades. Treatment with nanomolar concentrations of βAP(1-40) induced a 75% decrease in PKCα, but not PKCγ, immunoreactivity in AC fibroblasts. In the AD fibroblasts, a 70% reduction of the PKCγ, but not PKCα, immunoreactivity was observed after βAP treatment. Preincubation of AC or AD fibroblasts with 50 μM lactacystine, a selective proteasome inhibitor, prevented β-AP(1-40)-mediated degradation of PKCα in the AC cells, and PKCγ in the AD fibroblasts. The effects of βAP(1-40) on PKCα in AC fibroblasts were prevented by inhibition of protein synthesis and reversed by PKC activation. A 3-hr treatment with 100 nM phorbol 12-myristate 13-acetate restored the PKCα signal in treated AC cells but it did not reverse the effects of βAP(1-40) on PKCγ in the AD fibroblasts. Pretreatment with the protein synthesis inhibitor, cycloheximide (CHX, 100 μM), inhibited the effects of βAP(1-40) on PKCα and blocked the rescue effect of phorbol 12-myristate 13-acetate in AC fibroblasts but did not modify PKCγ immunoreactivity in AD cells. These results suggest that βAP(1-40) differentially affects PKC regulation in AC and AD cells via proteolytic degradation and that PKC activation exerts a protective role via de novo protein synthesis in normal but not AD cells.
- Publication:
-
Proceedings of the National Academy of Science
- Pub Date:
- May 1998
- DOI:
- 10.1073/pnas.95.10.5562
- Bibcode:
- 1998PNAS...95.5562F