PKC? promotes HuD-mediated neprilysin mRNA stability and enhances neprilysin-induced A? degradation in brain neurons.
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ABSTRACT: Amyloid-beta (A?) peptide accumulation in the brain is a pathological hallmark of all forms of Alzheimer's disease. An imbalance between A? production and clearance from the brain may contribute to accumulation of neurotoxic A? and subsequent synaptic loss, which is the strongest correlate of the extent of memory loss in AD. The activity of neprilysin (NEP), a potent A?-degrading enzyme, is decreased in the AD brain. Expression of HuD, an mRNA-binding protein important for synaptogenesis and neuronal plasticity, is also decreased in the AD brain. HuD is regulated by protein kinase C? (PKC?), and we previously demonstrated that PKC? activation decreases A? levels. We hypothesized that PKC? acts through HuD to stabilize NEP mRNA, modulate its localization, and support NEP activity. Conversely, loss of PKC?-activated HuD in AD leads to decreased NEP activity and accumulation of A?. Here we show that HuD is associated with NEP mRNA in cultures of human SK-N-SH cells. Treatment with bryostatin, a PKC?-selective activator, enhanced NEP association with HuD and increased NEP mRNA stability. Activation of PKC? also increased NEP protein levels, increased NEP phosphorylation, and induced cell surface expression. In addition, specific PKC? activation directly stimulated NEP activity, leading to degradation of a monomeric form of A? peptide and decreased A? neuronal toxicity, as measured by cell viability. Bryostatin treatment also rescued A?-mediated inhibition of HuD-NEP mRNA binding, NEP protein expression, and NEP cell membrane translocation. These results suggest that PKC? activation reduces A? by up-regulating, via the mRNA-binding protein HuD, A?-degrading enzymes such as NEP. Thus, PKC? activation may have therapeutic efficacy for AD by reducing neurotoxic A? accumulation as well as having direct anti-apoptotic and synaptogenic effects.
SUBMITTER: Lim CS
PROVIDER: S-EPMC4029802 | biostudies-literature | 2014
REPOSITORIES: biostudies-literature
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