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Using peptide nucleic acids as gene-expression modifiers to reduce beta-amyloid levels.

  • McMahon, Beth M
  • Stewart, Jennifer
  • Fauq, Abdul
  • Younkin, Steven
  • Younkin, Linda
  • Richelson, Elliott
Published Article
Journal of molecular neuroscience : MN
Publication Date
Jan 01, 2002
PMID: 12212797


The deposition of amyloid beta peptide (A beta) is an early and critical aspect of Alzheimer's disease. A beta is formed by the cleavage of amyloid precursor protein (APP). Studies of familial forms of Alzheimer's disease indicate that elevated secretion of A beta, particularly A beta(1-42), is likely to be an etiologic agent in the disease. A beta(1-42) is known to cause fibril formation and at elevated levels increases aggregation, which can lead to neuronal death. It has, therefore, been hypothesized that if the levels of A betaB, particularly A beta(1-42), could be reduced that onset of Alzheimer's disease could be slowed or possibly prevented. We, therefore, propose using PNAs targeted to APP to decrease plasma and brain levels of A beta(1-40) and A beta(1-42). This research project is designed to expand upon the discovery in our laboratory that systemic administration of antisense or antigene treatments utilizing peptide nucleic acids (PNAs) can be used to target and shut down proteins. Antisense strategies are methods of specifically targeting a particular protein by inhibiting translation by complementary binding to mRNA, while antigene methods inhibit transcription by complementary binding to DNA. For experiments involving antisense strategies, there are several advantages to using PNAs as opposed to the traditional oligonucleotide approaches. We initially preformed our studies in rats and identified a PNA sequence that was able to significantly reduce the levels of A beta(1-41) in rat brain compared to vehicle control rats. We have switched to mice so that we can prepare to perform our experiments in a transgenic animal model of Alzheimer's disease. We have, however, run into several technical difficulties with using mice compared to rats. In spite of this, we have identified one PNA sequence that specifically lowers mouse brain A beta(1-40) A beta(1-42) by 37% and 47%, respectively.

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