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.
Araki
Wataru
W
Department of Demyelinating Disease and Aging, National Institute of Neuroscience, Tokyo 187-8502, Japan. araki@ncnp.go.jp
Kametani
Fuyuki
F
Oda
Akiko
A
Tamaoka
Akira
A
D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry* / Q000378:metabolism*; D001549:Benzamides / Q000494:pharmacology; D002070:Butadienes / Q000494:pharmacology; D045744:Cell Line, Tumor; D006801:Humans; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D009570:Nitriles / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects
C120227:2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluorobenzamide; D016564:Amyloid beta-Protein Precursor; D001549:Benzamides; D002070:Butadienes; D009570:Nitriles; D047428:Protein Kinase Inhibitors; C113580:U 0126; D020929:Mitogen-Activated Protein Kinase Kinases; D053829:Amyloid Precursor Protein Secretases; D046988:Proteasome Endopeptidase Complex