Silencing of amyloid precursor protein expression using a new engineered delta ribozyme

Abstract

Alzheimer's disease (AD) etiological studies suggest that an elevation in amyloid- peptides (A) level contributes to aggregations of the peptide and subsequent development of the disease. The major constituent of these amyloid peptides is the 1 to 40-42 residue peptide (A40-42) derived from amyloid protein precursor (APP). Most likely, reducing A levels in the brain may block both its aggregation and neurotoxicity and would be beneficial for patients with AD. Among the several possible ways to lower A accumulation in the cells, we have selectively chosen to target the primary step in the A cascade, namely, to reduce APP gene expression. Toward this end, we engineered specific SOFA-HDV ribozymes, a new generation of catalytic RNA tools, to decrease APP mRNA levels. Additionally, we demonstrated that APP-ribozymes are effective at decreasing APP mRNA and protein levels as well as A levels in neuronal cells. Our results could lay the groundwork for a new protective treatment for AD. © 2012 Manel Ben Aissa et al.