Regulated formation of Golgi secretory vesicles containing Alzheimer beta-amyloid precursor protein.
Phorbol esters, activators of protein kinase C (PKC), regulate the relative utilization of alternative processing pathways for the Alzheimer beta-amyloid precursor protein (beta-APP) in intact cells, increasing the production of nonamyloidogenic soluble beta-APP (s beta-APP) and decreasing that of neurotoxic beta-amyloid (A beta) peptide. The molecular and cellular bases of PKC-regulated beta-APP cleavage are poorly understood. Here we demonstrate in a reconstituted cell-free system that activation of endogenous PKC increases formation from the trans-Golgi network of secretory vesicles containing beta-APP and that this effect can be mimicked by purified PKC. The results demonstrate directly that PKC is involved in regulation of secretory vesicle formation and provide a mechanism by which PKC may reduce the formation of the A beta peptide characteristic of Alzheimer disease.
Xu
H
H
Department of Neurology and Neuroscience, Cornell University Medical College, New York, New York 10021, USA.
Greengard
P
P
Gandy
S
S
D017607:Aluminum Compounds / Q000494:pharmacology; D000544:Alzheimer Disease / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D001693:Biological Transport, Active; D002474:Cell-Free System; D004789:Enzyme Activation / Q000187:drug effects; D005459:Fluorides / Q000494:pharmacology; D006056:Golgi Apparatus / Q000187:drug effects / Q000378:metabolism*; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000494:pharmacology; D006801:Humans; D016716:PC12 Cells; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats
D017607:Aluminum Compounds; D016564:Amyloid beta-Protein Precursor; D015240:Phorbol 12,13-Dibutyrate; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D011493:Protein Kinase C; D005459:Fluorides; C032311:aluminum fluoride