Protein kinases A and C regulate amyloid-β degradation by modulating protein levels of neprilysin and insulin-degrading enzyme in astrocytes.

Neuroscience Research
Naoki YamamotoKazuya Sobue

Abstract

The pathology of sporadic Alzheimer's disease is hallmarked by altered signal transduction via the neurotransmitter receptor-G-protein-mediated protein kinase A (PKA) and protein kinase C (PKC) pathways. Because the accumulation of amyloid-β (Aβ) depends on its rates of synthesis and clearance, the metabolic pathway of Aβ in the brain and the entire body warrants exploration. The two major enzymes involved in Aβ degradation in the brain are believed to be the neprilysin and insulin-degrading enzyme (IDE). This study investigated whether PKA and PKC regulate the degradation of Aβ by modulating the protein levels of neprilysin and IDE in astrocytes. Activation of PKA induced a significant decrease in neprilysin protein levels in cultured astrocytes, whereas activation of PKC induced a significant decrease in the protein level of neprilysin and an increase in the protein level of IDE. Following activation of PKC, the reduction of neprilysin was achieved by its secretion into the culture media. Moreover, PKA-activated astrocytes significantly delayed the degradation of exogenous Aβ, whereas PKC-activated astrocytes significantly facilitated its degradation. These results suggest that PKA and PKC regulate Aβ degradation in astrocyte...Continue Reading

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