PMID- 15314261
OWN - NLM
STAT- MEDLINE
DCOM- 20041230
LR  - 20220318
IS  - 0895-8696 (Print)
IS  - 0895-8696 (Linking)
VI  - 24
IP  - 1
DP  - 2004
TI  - FDA-preapproved drugs targeted to the translational regulation and processing of 
      the amyloid precursor protein.
PG  - 129-36
AB  - The 5' untranslated region (5'UTR) of the transcript encoding the Alzheimer's 
      amyloid precursor protein (APP) is a key regulatory sequence that determines the 
      amount of intracellular APP holoprotein present in brain derived cells. Using 
      neuroblastoma cells (SY5Y) we developed a transfection based screen of a library 
      of FDA drugs to identify compounds that limited APP luciferase reporter 
      expression translated from the APP 5'UTR. Paroxetine (Paxil trade mark ), 
      dimercaptopropanol, phenserine, desferrioxamine, tetrathiolmobdylate, and 
      azithromycin were six leads that were subsequently found to also suppress APP 
      holoprotein levels or to alter APP cleavage (azithromycin). Since APP holoprotein 
      levels are proportionate to Abeta peptide output in many systems we tested the 
      efficacy of paroxetine and dimercaptopropanol to limit Abeta secretion as 
      measured by ELISA assays. Paroxetine and dimercaptopropanol limited Abeta peptide 
      secretion from lens epithelial cells (B3 cells). Interestingly, paroxetine 
      changed the steady-state levels of transferrin receptor mRNAs. These data 
      suggested that this serotonin reuptake inhibitor (SSRI) provided extra 
      pharmacological action to chelate interacellular iron or change the intracellular 
      iron distribution. An altered iron distribution would be predicted to indirectly 
      limit APP holoprotein expression and Abeta peptide secretion.
CI  - Copyright 2004 Humana Press Inc.
FAU - Morse, Lee Jae
AU  - Morse LJ
AD  - Laboratory for Functional Genomics, Brigham and Women's Hospital, Harvard Medical 
      School, USA.
FAU - Payton, Sandra M
AU  - Payton SM
FAU - Cuny, Gregory D
AU  - Cuny GD
FAU - Rogers, Jack T
AU  - Rogers JT
LA  - eng
GR  - R01 AG21081-01A1/AG/NIA NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - J Mol Neurosci
JT  - Journal of molecular neuroscience : MN
JID - 9002991
RN  - 0 (5' Untranslated Regions)
RN  - 0 (Amyloid beta-Peptides)
RN  - 0 (Amyloid beta-Protein Precursor)
RN  - 0 (Chelating Agents)
RN  - 0 (Neuroprotective Agents)
RN  - 0 (Organometallic Compounds)
RN  - 0 (Protein Synthesis Inhibitors)
RN  - 0 (RNA, Messenger)
RN  - 0 (Receptors, Transferrin)
RN  - 0CPP32S55X (Dimercaprol)
RN  - 41VRH5220H (Paroxetine)
RN  - 94157-11-6 (dimercaptopropanol-zinc complex)
RN  - E1UOL152H7 (Iron)
SB  - IM
MH  - 5' Untranslated Regions/drug effects/genetics
MH  - Alzheimer Disease/*drug therapy/genetics/metabolism
MH  - Amyloid beta-Peptides/*antagonists & inhibitors/metabolism
MH  - Amyloid beta-Protein Precursor/*antagonists & inhibitors/genetics/metabolism
MH  - Animals
MH  - Cell Line, Tumor
MH  - Chelating Agents/pharmacology
MH  - Dimercaprol/*analogs & derivatives/pharmacology/therapeutic use
MH  - Dose-Response Relationship, Drug
MH  - Down-Regulation/drug effects/genetics
MH  - Drug Evaluation, Preclinical
MH  - Epithelial Cells/drug effects/metabolism
MH  - Humans
MH  - Iron/metabolism
MH  - Neuroprotective Agents/*pharmacology/therapeutic use
MH  - Organometallic Compounds/pharmacology/therapeutic use
MH  - Paroxetine/pharmacology/therapeutic use
MH  - Protein Biosynthesis/*drug effects/genetics
MH  - Protein Processing, Post-Translational/drug effects
MH  - Protein Synthesis Inhibitors/*pharmacology/therapeutic use
MH  - RNA, Messenger/drug effects/metabolism
MH  - Receptors, Transferrin/genetics
EDAT- 2004/08/18 05:00
MHDA- 2004/12/31 09:00
CRDT- 2004/08/18 05:00
PHST- 2004/08/18 05:00 [pubmed]
PHST- 2004/12/31 09:00 [medline]
PHST- 2004/08/18 05:00 [entrez]
AID - JMN:24:1:129 [pii]
AID - 10.1385/JMN:24:1:129 [doi]
PST - ppublish
SO  - J Mol Neurosci. 2004;24(1):129-36. doi: 10.1385/JMN:24:1:129.