Metal specificity of an iron-responsive element in Alzheimer's APP mRNA 5'untranslated region, tolerance of SH-SY5Y and H4 neural cells to desferrioxamine, clioquinol, VK-28, and a piperazine chelator.
Iron closely regulates the expression of the Alzheimer's Amyloid Precursor Protein (APP) gene at the level of message translation by a pathway similar to iron control of the translation of the ferritin L- and H mRNAs by Iron-responsive Elements in their 5' untranslated regions (5'UTRs). Using transfection based assays in SH-SY5Y neuroblastoma cells we tested the relative efficiency by which iron, copper and zinc up-regulate IRE activity in the APP 5'UTR. Desferrioxamine (high affinity Fe3+ chelator), (ii) clioquinol (low affinity Fe/Cu/Zn chelator), (iii) piperazine-1 (oral Fe chelator), (iv) VK-28 (oral Fe chelator), were tested for their relative modulation of APP 5' UTR directed translation of a luciferase reporter gene. Iron chelation based therapeutic strategies for slowing the progression of Alzheimer's disease (and other neurological disorders that manifest iron imbalance) are discussed with regard to the relative neural toxic action of each chelator in SH-SY5Y cells and in H4 glioblastoma cells.
Bandyopadhyay
S
S
Neurochemistry Laboratory, Department of Psychiatry, Genetics and Aging Research Unit, Massachusetts General Hospital 2 NIA, Baltimore, MD, USA.
Huang
X
X
Cho
H
H
Greig
N H
NH
Youdim
M B
MB
Rogers
J T
JT
D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D007464:Clioquinol / Q000494:pharmacology; D003676:Deferoxamine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005909:Glioblastoma; D006801:Humans; D007502:Iron Chelating Agents / Q000494:pharmacology*; D035925:Iron-Regulatory Proteins / Q000378:metabolism*; D008958:Models, Molecular; D009447:Neuroblastoma; D014176:Protein Biosynthesis / Q000187:drug effects*; D012333:RNA, Messenger / Q000378:metabolism*; D014162:Transfection / Q000379:methods; D020506:Untranslated Regions / Q000235:genetics / Q000378:metabolism*
D016564:Amyloid beta-Protein Precursor; D007502:Iron Chelating Agents; D035925:Iron-Regulatory Proteins; D012333:RNA, Messenger; D020506:Untranslated Regions; D007464:Clioquinol; D003676:Deferoxamine