Oxidative Stress Induces Increase in Intracellular Amyloid β-Protein Production and Selective Activation of βI and βII PKCs in NT2 Cells

• Published in: Biochemical and biophysical research communications 2000-02, Vol.268 (2), p.642-646
• Main Authors: Paola, Dimitri, Domenicotti, Cinzia, Nitti, Mariapaola, Vitali, Antonella, Borghi, Roberta, Cottalasso, Damiano, Zaccheo, Damiano, Odetti, Patrizio, Strocchi, Paola, Marinari, Umberto M., Tabaton, Massimo, Pronzato, Maria A.
• Format: Article
• Language: English
• Subjects: 4-hydroxy-2,3-nonenal; Alzheimer's disease; amyloid precursor protein; amyloid β protein; oxidative stress; protein kinase C
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1006/bbrc.2000.2164

Amyloid β-protein (Aβ) aggregation produces an oxidative stress in neuronal cells that, in turn, may induce an amyloidogenic shift of neuronal metabolism. To investigate this hypothesis, we analyzed intra- and extracellular Aβ content in NT2 differentiated cells incubated with 4-hydroxy-2,3-nonenal (HNE), a major product of lipid peroxidation. In parallel, we evaluated protein kinase C (PKC) isoenzymes activity, a signaling system suspected to modulate amyloid precursor protein (APP) processing. Low HNE concentrations (0.1–1 μM) induced a 2–6 fold increase of intracellular Aβ production that was concomitant with selective activation of βI and βII PKC isoforms, without affecting either cell viability or APP full-length expression. Selective activation of the same PKC isoforms was observed following NT2 differentiation. Our findings suggest that PKC β isoenzymes are part of cellular mechanisms that regulate production of the intracellular Aβ pool. Moreover, they indicate that lipid peroxidation fosters intracellular Aβ accumulation, creating a vicious neurodegenerative loop.