Activation of protein kinase C modulates BACE1-mediated beta-secretase activity.
beta-Site APP cleavage enzyme 1 (BACE1) is the beta-secretase responsible for generating amyloid-beta (A beta) peptides in Alzheimer's disease (AD). Previous studies suggest that activation of protein kinase C (PKC) modulates the beta-secretase-mediated cleavage of APP and reduces the production of A beta. The mechanism of PKC-mediated modulation of beta-secretase activity, however, remains elusive. We report here that activation of PKC modulated beta-secretase activity through either suppressing the accumulation or promoting the translocation of BACE1 protein in a cell type-dependent manner. We found that activation of PKC suppressed the accumulation of BACE1 protein in fibroblasts through an enhancement of intracellular protease activities. In neurons, activation of PKC did not alter the expression level of BACE1, but led to more BACE1 translocated to the cell surface, resulting in a decreased cleavage of APP at the beta1 site. Together, Our findings provide novel mechanisms of PKC-mediated modulation of beta-secretase activity, suggesting that alteration of the intracellular trafficking of BACE1 may serve as a useful therapeutic strategy to lower the production of A beta in AD.
Wang
Lizhen
L
Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892-3707, USA.
Shim
Hoon
H
Xie
Chengsong
C
Cai
Huaibin
H
D053829:Amyloid Precursor Protein Secretases / Q000172:deficiency / Q000378:metabolism* / Q000502:physiology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D016282:Aspartic Acid Endopeptidases / Q000172:deficiency / Q000502:physiology*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D009474:Neurons / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D011493:Protein Kinase C / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014162:Transfection / Q000379:methods
D016229:Amyloid beta-Peptides; D004791:Enzyme Inhibitors; D011493:Protein Kinase C; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse; D013755:Tetradecanoylphorbol Acetate