Protein kinase C and amyloid precursor protein processing in skin fibroblasts from sporadic and familial Alzheimer's disease cases.
Non-amyloidogenic alpha-secretase processing of amyloid precursor protein (APP) is stimulated by protein kinase C (PKC). Levels and activity of PKC are decreased in sporadic Alzheimer's disease skin fibroblasts. We investigated whether alterations in PKC and PKC-mediated APP processing occur also in fibroblasts established from individuals with familial Alzheimer's disease APP KM670/671NL, PS1 M146V and H163Y mutations. These pathogenic mutations are known to alter APP metabolism to increase Abeta. PKC activities, but not levels, were decreased by 50% in soluble fractions from sporadic Alzheimer's disease cases. In contrast, familial Alzheimer's disease fibroblasts showed no significant changes in PKC enzyme activity. Fibroblasts bearing the APP KM670/671NL mutation showed no significant differences in either PKC levels or PKC-mediated soluble APP (APPs) secretion, compared to controls. Fibroblasts bearing PS1 M146V and H163Y mutations showed a 30% increase in soluble PKC levels and a 40% decrease in PKC-mediated APPs secretion. These results indicate that PKC deficits are unlikely to contribute to increased Abeta seen with APP and PS1 mutations, and also that PS1 mutations decrease alpha-secretase derived APPs production independently of altered PKC activity.
Vestling
M
M
Division of Geriatric Medicine, Karolinska Institute, Novum, KFC, Plan 4, S-141 86, Huddinge, Sweden.
Cedazo-Mínguez
A
A
Adem
A
A
Wiehager
B
B
Racchi
M
M
Lannfelt
L
L
Cowburn
R F
RF
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000201:enzymology* / Q000235:genetics; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; D002478:Cells, Cultured; D003470:Culture Media / Q000737:chemistry; D010450:Endopeptidases / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts / Q000201:enzymology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011493:Protein Kinase C / Q000032:analysis / Q000378:metabolism*; D012867:Skin / Q000201:enzymology*; D013548:Sweden
D003470:Culture Media; D011493:Protein Kinase C; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human