PMID- 7970175
OWN - NLM
STAT- MEDLINE
DCOM- 19941229
LR  - 20190701
IS  - 0304-3940 (Print)
IS  - 0304-3940 (Linking)
VI  - 174
IP  - 2
DP  - 1994 Jun 20
TI  - Reversal of the Swedish familial Alzheimer's disease mutant phenotype in cultured 
      cells treated with phorbol 12,13-dibutyrate.
PG  - 173-6
AB  - Protein phosphorylation mediated by phorbol ester stimulates secretion of the 
      beta-amyloid precursor protein (beta-APP) in the cell culture. This increase in 
      secretion is produced by a transient increase in cleavage to produce 
      non-amyloidogenic protease nexin II products mediated by the alpha-secretase 
      activity, and a concomitant decrease in beta-protein production. Cells expressing 
      the Swedish familial Alzheimer's disease (FAD) variant of beta-APP produce more 
      beta-protein and potentially amyloidogenic fragments than cells expressing 
      wild-type protein; furthermore, cleavage shifts from the alpha- to the 
      beta-secretase cleavage site of the precursor. We show that treatment with 
      phorbol 12,13-dibutyrate (PDBu) of cells expressing the Swedish FAD reverses the 
      mutant phenotype to wild-type. The alpha-secretase cleavage increases with a 
      concomitant loss of beta-protein and other beta-secretase cleaved products. These 
      results show that modulating beta-secretase cleavage directly affects 
      beta-protein production. It suggests that activating protein kinase C through, 
      for example, muscarinic receptor agonists could reduce amyloidosis by modulating 
      the level of beta-protein produced.
FAU - Felsenstein, K M
AU  - Felsenstein KM
AD  - CNS - Department of Biophysics and Molecular Biology, Bristol-Myers Squibb 
      Pharmaceutical Research Institute, Wallingford, CT 06492.
FAU - Ingalls, K M
AU  - Ingalls KM
FAU - Hunihan, L W
AU  - Hunihan LW
FAU - Roberts, S B
AU  - Roberts SB
LA  - eng
PT  - Journal Article
PL  - Ireland
TA  - Neurosci Lett
JT  - Neuroscience letters
JID - 7600130
RN  - 0 (Amyloid beta-Peptides)
RN  - 0 (Cholinergic Antagonists)
RN  - 37558-16-0 (Phorbol 12,13-Dibutyrate)
RN  - EC 2.7.11.13 (Protein Kinase C)
SB  - IM
MH  - Alzheimer Disease/*genetics
MH  - Amyloid beta-Peptides/genetics/metabolism
MH  - Cells, Cultured
MH  - Cholinergic Antagonists/pharmacology
MH  - Humans
MH  - Immunoblotting
MH  - Mutation/*drug effects
MH  - Phenotype
MH  - Phorbol 12,13-Dibutyrate/*pharmacology
MH  - Protein Kinase C/genetics/metabolism
MH  - Sweden
EDAT- 1994/06/20 00:00
MHDA- 1994/06/20 00:01
CRDT- 1994/06/20 00:00
PHST- 1994/06/20 00:00 [pubmed]
PHST- 1994/06/20 00:01 [medline]
PHST- 1994/06/20 00:00 [entrez]
AID - 0304-3940(94)90014-0 [pii]
AID - 10.1016/0304-3940(94)90014-0 [doi]
PST - ppublish
SO  - Neurosci Lett. 1994 Jun 20;174(2):173-6. doi: 10.1016/0304-3940(94)90014-0.