Alzheimer’s-specific effects of soluble β-amyloid on protein kinase C-α and -γ degradation in human fibroblasts

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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.