Action of amyloid beta-protein on protein kinase C activity.
Amyloid beta-protein (A beta), the major protein of cerebrovascular and plaque amyloid in Alzheimer disease, is considered a primary factor in the pathology of this disease. The effect of synthetic A beta (1-40) on the activity of protein kinase C (PKC) was studied with histones for a substrate in a mixed micellar assay, and with calmodulin-depleted soluble brain proteins in a liposomal system. We report here that A beta affects PKC activity in a biphasic manner. An initial stimulation of PKC was noted at low concentrations of A beta (less than 2.5 microM); while PKC-inhibition was observed in a concentration-dependent manner at higher concentrations of A beta. The in vitro phosphorylation of 20, 47, and 87 kDa brain proteins (known PKC substrates) was significantly reduced by 60 microM A beta. The role of 20 kDa in memory storage, of 87 kDa in neurotransmission and neurosecretory processes, and of 47 kDa in long-term potentiation or memory is well recognized, and A beta is known to have both neurotrophic and neurotoxic effects. Since PKC plays an important role in neuronal function, it is suggested that dual modulation of PKC by A beta may be linked to its neurotrophic and neurotoxic effects. We propose that at low concentrations A beta, by stimulating PKC, may contribute to neurites generation; and at higher concentrations A beta, by inhibiting PKC activity, might lead first to memory impairment, and then to neuronal loss.
New York State Institute for Basic Research in Developmental Disabilities, Staten Island 10314.
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Chauhan
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Chauhan
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Brockerhoff
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Wisniewski
D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D001923:Brain Chemistry; D004305:Dose-Response Relationship, Drug; D006657:Histones / Q000378:metabolism; D008969:Molecular Sequence Data; D010766:Phosphorylation / Q000187:drug effects; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism*; D051381:Rats
D016229:Amyloid beta-Peptides; D006657:Histones; D011506:Proteins; D011493:Protein Kinase C