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

Abstract 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.