MEK inhibitors suppress beta-amyloid production by altering the level of a beta-C-terminal fragment of amyloid precursor protein in neuronal cells.

Beta-amyloid peptide (Abeta) is generated via sequential proteolysis of amyloid precursor protein (APP) by beta- and gamma-secretases. Cell-based screening experiments disclosed that the MEK (MAP kinase kinase) inhibitors, U0126 and PD184352, suppress Abeta secretion from human neuronal SH-SY5Y cells expressing Swedish mutant APP. These inhibitors did not affect the cellular levels of APP but significantly reduced those of the APP beta-C-terminal fragment (beta-CTF). Additionally, beta-CTF levels were markedly reduced by these inhibitors in cells expressing the fragment in a gamma-secretase-independent and proteasome-dependent manner. Our results suggest that MEK inhibitors reduce Abeta generation via secretase-independent alteration of beta-CTF levels.