Al Khashali_2022_Int.J.Mol.Sci_23_

In comparing two human lung cancer cells, we previously found lower levels of acetylcholinesterase (AChE) and intact amyloid-beta40/42 (Abeta), 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 (sAPPalpha) are regulated by AChE and mBDNF in A549 and H1299 cell media. The levels of sAPPalpha were higher in the media of H1299 cells. Knockdown of AChE led to increased sAPPalpha and mBDNF levels and correlated with decreased levels of intact Abeta40/42 in A549 cell media. AChE and mBDNF had opposite effects on the levels of Abeta and sAPPalpha and were found to operate through a mechanism involving alpha-secretase activity. Treatment with AChE decreased sAPPalpha levels and simultaneously increased the levels of intact Abeta40/42 suggesting a role of the protein in shifting APP processing away from the non-amyloidogenic pathway and toward the amyloidogenic pathway, whereas treatment with mBDNF led to opposite effects on those levels. We also show that the levels of sAPPalpha 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).