Regulation of the Soluble Amyloid Precursor Protein alpha (sAPP alpha) Levels by Acetylcholinesterase and Brain-Derived Neurotrophic Factor in Lung Cancer Cell Media

In comparing two human lung cancer cells, we previously found lower levels of acetylcholinesterase (AChE) and intact amyloid-beta 40/42 (A beta), and higher levels of mature brain-derived neurotrophic factor (mBDNF) in the media of H1299 cells as compared to A549 cell media. In this study, we hypothesized that the levels of soluble amyloid precursor protein alpha (sAPP alpha) are regulated by AChE and mBDNF in A549 and H1299 cell media. The levels of sAPP alpha were higher in the media of H1299 cells. Knockdown of AChE led to increased sAPP alpha and mBDNF levels and correlated with decreased levels of intact A beta 40/42 in A549 cell media. AChE and mBDNF had opposite effects on the levels of A beta and sAPP alpha and were found to operate through a mechanism involving alpha-secretase activity. Treatment with AChE decreased sAPP alpha levels and simultaneously increased the levels of intact A beta 40/42 suggesting a role of the protein in shifting APP processing away from the nonamyloidogenic pathway and toward the amyloidogenic pathway, whereas treatment with mBDNF led to opposite effects on those levels. We also show that the levels of sAPP alpha are regulated by protein kinase C (PKC), extracellular signal-regulated kinase (ERK)1/2, phosphoinositide 3 Kinase (PI3K), but not by protein kinase A (PKA).