ABSTRACT
Alzheimer's disease (AD) etiological studies suggest that an elevation in amyloid-ß peptides (Aß) 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 (Aß(40-42)) derived from amyloid protein precursor (APP). Most likely, reducing Aß 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 Aß accumulation in the cells, we have selectively chosen to target the primary step in the Aß 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 Aß levels in neuronal cells. Our results could lay the groundwork for a new protective treatment for AD.
