Inhibition of the NGF and IL-1beta-induced expression of Alzheimer's amyloid precursor protein by antisense oligonucleotides.
Alzheimer's disease (AD) is a neurodegenerative disorder of the brain characterized by the extracellular deposition of amyloid in senile plaques and along the walls of the cerebral vasculature. The principal constituent of amyloid deposit is amyloid beta peptide (Abeta) derived from its larger precursor protein, amyloid precursor protein (APP). The overexpression of APP is known to be a risk factor for Abeta deposit in AD and in Down syndrome (DS). The inhibition of APP expression has been thought to be beneficial to patients with AD and DS. In this study, we investigated the effects of antisense oligonucleotide (AO) on the overexpression of APP induced by IL-1beta and NGF. Using phosphorothioate-oligonucleotides against initiation codon significantly reduced the protein levels of APP induced by NGF and IL-1beta to basal level in PC12 cell culture systems. These results showed that these antisense oligonucleotides may have a potential to be a therapeutic agent for some patients with AD and DS.
Chang
K A
KA
Department of Pharmacology, College of Medicine, Neuroscience Research Institute, MRC, Seoul National University, Korea.
Kim
S H
SH
Sakaki
Y
Y
Kim
H S
HS
Park
C W
CW
Suh
Y H
YH
D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D000818:Animals; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D009414:Nerve Growth Factors / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D009447:Neuroblastoma; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology*; D016716:PC12 Cells; D051381:Rats; D013873:Thionucleotides; D014407:Tumor Cells, Cultured
D016564:Amyloid beta-Protein Precursor; D007375:Interleukin-1; D009414:Nerve Growth Factors; D020319:Oligodeoxyribonucleotides, Antisense; D013873:Thionucleotides