Peptide nucleic acids targeted to the amyloid precursor protein.
The depositing in brain of amyloid beta peptide (Abeta), which is formed by the cleavage of amyloid precursor protein (APP), is likely an etiologic factor in Alzheimer's disease (AD). Of the different forms of Abeta, Abeta(1-42) causes fibril formation and increases aggregation at elevated levels, which can lead to neuronal death. It is hypothesized that if the levels of Abeta, particularly Abeta(1-42), were reduced, then the onset of AD would be slowed or possibly prevented. Therefore, we are using peptide nucleic acids (PNAs) targeted to APP, as well as other key proteins, to try to decrease plasma and brain levels of Abeta(1-40) and Abeta(1-42). This research project was designed to utilize the expertise of our laboratory in the use of PNAs, a third-generation antisense or antigene molecule, to knock down proteins in brain. Antisense compounds specifically knock down the expression of a particular protein by inhibiting translation at the level of mRNA. On the other hand, antigene compounds knock down expression at the level of transcription. For experiments involving antisense strategies, there are several advantages to using PNAs as opposed to the traditional oligonucleotide molecules. We report here the ongoing studies with mice and rats with PNAs targeting APP, as well as BACE.
D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D016375:Antisense Elements (Genetics) / Q000494:pharmacology / Q000627:therapeutic use; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D010446:Peptide Fragments / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000378:metabolism; D020135:Peptide Nucleic Acids / Q000494:pharmacology* / Q000627:therapeutic use; D014176:Protein Biosynthesis / Q000187:drug effects / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D016375:Antisense Elements (Genetics); D010446:Peptide Fragments; D020135:Peptide Nucleic Acids; D012333:RNA, Messenger; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D016282:Aspartic Acid Endopeptidases