FDA-preapproved drugs targeted to the translational regulation and processing of the amyloid precursor protein.
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.
Morse
Lee Jae
LJ
Laboratory for Functional Genomics, Brigham and Women's Hospital, Harvard Medical School, USA.
Payton
Sandra M
SM
Cuny
Gregory D
GD
Rogers
Jack T
JT
D020121:5' Untranslated Regions / Q000187:drug effects / Q000235:genetics; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D002614:Chelating Agents / Q000494:pharmacology; D004112:Dimercaprol / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D004353:Drug Evaluation, Preclinical; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007501:Iron / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D009942:Organometallic Compounds / Q000494:pharmacology / Q000627:therapeutic use; D017374:Paroxetine / Q000494:pharmacology / Q000627:therapeutic use; D014176:Protein Biosynthesis / Q000187:drug effects* / Q000235:genetics; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D011990:Receptors, Transferrin / Q000235:genetics
D020121:5' Untranslated Regions; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D002614:Chelating Agents; D018696:Neuroprotective Agents; D009942:Organometallic Compounds; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D011990:Receptors, Transferrin; D004112:Dimercaprol; D017374:Paroxetine; C088066:dimercaptopropanol-zinc complex; D007501:Iron