Cryptotanshinione upregulates alpha-secretase by activation PI3K pathway in cortical neurons

The amyloid precursor protein (APP) is cleaved enzymatically by nonamyloidogenic and amyloidogenic pathways. alpha-Secretase cleaves APP within beta amyloid protein (Abeta) sequence, resulting in the release of a secreted fragment of APP (sAPPalpha) and precluding Abeta generation. Cryptotanshinone (CTS), an active component of the medicinal herb Salvia miltiorrhiza, has been shown to improve learning and memory in several pharmacological models of Alzheimer's disease (AD). We have shown previously that CTS modulated APP metabolism by elevation alpha-secretase activity. However, the molecular mechanisms involved were unclear. Here we reported that CTS increased alpha-secretase activity and sAPPalpha release. To gain insight into the molecular mechanism whereby CTS modulates alpha-secretase, we evaluated the involvement of three candidate alpha-secretase enzymes, a-disintegrin and metalloprotease (ADAM) 9, 10, or 17, in CTS-induced non-amyloidogenic APP metabolism. Results showed that CTS treatment of cortical neurons overexpressing Swedish mutant human APP695 markedly elevated ADAM10 protein, and the inhibitor of ADAM10 inhibited the CTS-induced increase in alpha-secretase activity, suggesting CTS modulated alpha-secretase activity by upregulation ADAM10 protein. By using several specific protein kinase inhibitors, we showed that phosphatidylinositol 3-kinase (PI3K) mediated the CTS-induced alpha-secretase activation.