The release of Alzheimer's disease beta amyloid peptide is reduced by phorbol treatment.
Amyloid precursor protein (APP) is cleaved predominantly within the beta amyloid peptide (BAP) domain to release a non-amyloidogenic amino-terminal PN2 fragment. Treatment of cells with phorbol dibutyrate, an agent which activates protein kinase C, has been shown to increase the release of an amino-terminal fragment. A panel of mutant APP reporter constructs was expressed in which each of the potential phosphorylation sites located within the cytoplasmic domain of APP was replaced with alanine residues. Phorbol response patterns were unchanged for each of these mutants, suggesting that induced cleavage occurs independently of APP substrate phosphorylation. We find that phorbol (a) increases the release of a PN2 fragment that is consistent with the normal secretase activity, (b) decreases the release of a shorter amino-terminal APP fragment that is cleaved near the amino terminus of BAP, and (c) decreases the release of BAP which was identified based on electrophoretic mobility, epitope mapping, and radio-sequencing. These data demonstrate that pharmacological treatment can reduce the formation of BAP and suggests that protein kinase C activators could be developed as therapeutic agents to block BAP formation.
Jacobsen
J S
JS
Department of Central Nervous System Biological Research, American Cyanamid Company, Pearl River, New York 10965.
Spruyt
M A
MA
Brown
A M
AM
Sahasrabudhe
S R
SR
Blume
A J
AJ
Vitek
M P
MP
Muenkel
H A
HA
Sonnenberg-Reines
J
J
D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000096:biosynthesis* / Q000302:isolation & purification; D000818:Animals; D002460:Cell Line; D002522:Chlorocebus aethiops; D003001:Cloning, Molecular; D006801:Humans; D007668:Kidney; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D010446:Peptide Fragments / Q000302:isolation & purification / Q000378:metabolism; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology*; D017384:Sequence Deletion; D014407:Tumor Cells, Cultured
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D015240:Phorbol 12,13-Dibutyrate