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

The amyloid precursor protein (APP) is cleaved enzymatically by nonamyloidogenic and amyloidogenic pathways. α-Secretase cleaves APP within β amyloid protein (Aβ) sequence, resulting in the release of a secreted fragment of APP (sAPPα) and precluding Aβ 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 α-secretase activity. However, the molecular mechanisms involved were unclear. Here we reported that CTS increased α-secretase activity and sAPPα release. To gain insight into the molecular mechanism whereby CTS modulates α-secretase, we evaluated the involvement of three candidate α-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 α-secretase activity, suggesting CTS modulated α-secretase activity by upregulation ADAM10 protein. By using several specific protein kinase inhibitors, we showed that phosphatidylinositol 3-kinase (PI3K) mediated the CTS-induced α-secretase activation.