Neuronal beta-amyloid precursor protein gene expression: regulation by aurintricarboxylic acid.
beta-Amyloid precursor protein (beta-APP) and its derivative, amyloid beta-protein (beta-A4), may cause death of differentiated neurons and aurintricarboxylic acid (ATA), a metabolic inhibitor, improves neuronal survival. Therefore, we studied the effect of ATA on neuronal beta-APP gene expression. ATA decreased beta-APP mRNA levels by increasing its degradation, without changing the rate of transcription. ATA decreased both steady state and interleukin-1 (IL1)-induced increase in beta-APP mRNA levels. These effects of ATA were associated with rounding of cells suggestive of decreased cell adhesion or neurite retraction that was completely reversible when ATA was removed. However, beta-APP mRNA levels continued to remain suppressed in neurons that were actively regrowing neurites following discontinuation of ATA. In studies carried out upto 24 h, ATA did not damage cells as determined by Trypan blue exclusion, lactate dehydrogenase (LDH)-release and transmission electron microscopy. The findings suggest that constitutive or steady state levels of beta-APP mRNA may not be essential for the survival and growth of neurons and that ATA suppresses beta-APP expression without causing cell damage. These observations may be a basis for studying whether ATA or a related compound could beneficially regulate beta-APP levels in vivo.
Joseph
R
R
Department of Neurology, Henry Ford Hospital, Detroit, MI 48202.
Tsang
W
W
Han
E
E
Saed
G M
GM
D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D001312:Aurintricarboxylic Acid / Q000494:pharmacology*; D001483:Base Sequence; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009447:Neuroblastoma; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism
D016564:Amyloid beta-Protein Precursor; D007375:Interleukin-1; D009419:Nerve Tissue Proteins; D001312:Aurintricarboxylic Acid