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.