Blockade of PKC epsilon activation attenuates phorbol ester-induced increase of alpha-secretase-derived secreted form of amyloid precursor protein.
The role of PKC epsilon in amyloid precursor protein (APP) processing was investigated using APP-overexpressing B103 cells. As reported previously, a PKC activator, phorbol-12,13-dibutyrate (PDBu), enhanced secretion of APP alpha, and this effect was blocked by a PKC inhibitor, GF109203X in this system. Selective inhibition of PKC epsilon by overexpressing the PKC epsilon V1 region, which binds specifically to the receptor for activated C-kinase (RACK), blocked PDBu-induced enhancement of APP alpha secretion as well as PDBu-induced decrease in beta-secretase-derived APP C-terminal fragment production. On the other hand, the level of PKC epsilon, but not that of PKC alpha or PKC gamma, was substantially lower in the brains of Alzheimer's disease patients compared to age-matched controls. These results add to a growing body of evidence that PKC epsilon plays an important role in modulating APP processing, and suggest that reduced PKC epsilon activity may contribute to the development of Alzheimer's disease.
Yeon
S W
SW
Brain Disease Research Center, Aju University School of Medicine, Suwon 442-721, Korea.
Jung
M W
MW
Ha
M J
MJ
Kim
S U
SU
Huh
K
K
Savage
M J
MJ
Masliah
E
E
Mook-Jung
I
I
D000544:Alzheimer Disease / Q000209:etiology / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D001483:Base Sequence; D001921:Brain / Q000201:enzymology; D016022:Case-Control Studies; D002460:Cell Line; D017931:DNA Primers / Q000235:genetics; D010450:Endopeptidases / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*; D051744:Protein Kinase C-epsilon; D011499:Protein Processing, Post-Translational; D051381:Rats; D014162:Transfection
D016564:Amyloid beta-Protein Precursor; D017931:DNA Primers; D007527:Isoenzymes; D015240:Phorbol 12,13-Dibutyrate; C497257:Prkce protein, rat; C497255:PRKCE protein, human; D011493:Protein Kinase C; D051744:Protein Kinase C-epsilon; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human