Degradation of Amyloid β-peptide (Aβ) by NEP-induction is increased by selected natural products

Neutral endopeptidase (EC 3.4.24.11, NEP) contributes to the degradation of amyloid beta-peptide in the brain [1]. Amyloid beta-peptide can be deposited as senile plaques in the brain leading to Alzheimer's disease (AD) [2]. The up-regulation of NEP in the brain may prevent AD development by increasing Amyloid beta-peptide clearance, resulting in a decrease of amyloid beta-peptide levels [3]. The aim of the present study was to investigate the cellular regulation of NEP expression in human neuroblastoma cell line SK-N-SH, focusing on the role of cyclic nucleotides. We studied the changes in the NEP activity after long-term treatment with substances, which increase the level of cyclic adenosine monophosphate (cAMP). The assay of NEP activity was determined according to Bormann and Melzig [4]. We determined the influence of some flavonoids as apigenin and luteolin, which are able to inhibit phosphodiesterase enzyme (PDE) [5], dibutylryl-cAMP (as protein kinase A activator [6]), forskolin (an adenylate cyclase activator [7]), and rolipram (a specific inhibitor of the phosphodiesterase type 4 isoform [8]) on the NEP activity. We could show that apigenin and luteolin induced NEP activity (up to 580%) with inhibition of cell proliferation. Whereas dibutylryl-cAMP, forskolin and rolipram induced the cellular NEP activity (up to 150%) and did not influence the proliferation. It is suggested that the enhancement of the cellular NEP activity might be correlated with an elevated level of cyclic adenosine monophosphate (cAMP) [9]. The results indicate, that the enhancement of the cellular NEP activity by apigenin and luteolin not only depends on the differentiation improvement but also on the direct influence on NEP gene expression via elevated level of intracellular cyclic Adenosine monophosphate (cAMP). The present data provide evidence for a cAMP-mediated increase of NEP activity in human neuroblastoma cells [10].

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