Down-regulation of amyloid precursor protein by peptide nucleic acid in vivo.
Alzheimer's disease (AD) is a neurodegenerative disease associated with increased expression of amyloid precursor protein (APP) and the deposition of its proteolytic cleavage products, the amyloid-beta peptides, Abeta(1-40) and Abeta(1-42). Peptide nucleic acids (PNAs) have been shown to block the expression of proteins at transcriptional and translational levels. In this study we used a sense and an antisense PNA specifically targeted to APP to inhibit the transcription and translation of APP by complementary binding to DNA or mRNA, respectively. Using Western blotting, APP showed a drastic decrease (50% and 90% reduction, in two separate experiments, as compared with saline control) with the injection of sense APP. mRNA levels were higher at the same time point after injection of APP sense PNA, most probably because of a compensatory mechanism in response to the drop of APP that might have occurred at an earlier time point (0-1 h) and was reflected in a drop at the protein level at 1 h. The injection of antisense PNA showed about 70% decrease in APP as measured by Western blotting. Unmodified PNA can be used in vivo to reduce the levels of APP, which plays a critical role in the development of AD.
Neuropsychopharmacology Laboratory, Mayo Foundation for Medical Education and Research, and Mayo Clinic Jacksonville, Jacksonville, FL 32224, USA.
Mona
M
Boules
Katrina
K
Williams
Elisa
E
Gollatz
Abdul
A
Fauq
Elliott
E
Richelson
D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D016375:Antisense Elements (Genetics) / Q000494:pharmacology / Q000627:therapeutic use; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D004247:DNA / Q000187:drug effects / Q000235:genetics; D015536:Down-Regulation / Q000187:drug effects* / Q000502:physiology; D008297:Male; D020135:Peptide Nucleic Acids / Q000494:pharmacology* / Q000627:therapeutic use; D014176:Protein Biosynthesis / Q000187:drug effects / Q000235:genetics; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics
D016564:Amyloid beta-Protein Precursor; D016375:Antisense Elements (Genetics); D020135:Peptide Nucleic Acids; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D004247:DNA