Silencing of Amyloid Precursor Protein Expression Using a New Engineered Delta Ribozyme

Manel Ben Aissa,Lucien-Junior Bergeron,Georges Levesque,Jean-Pierre Perreault,Marie-Claude April

doi:10.1155/2012/947147

Manel Ben Aissa, Lucien-Junior Bergeron + Show 3 more

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https://doi.org/10.1155/2012/947147

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Abstract

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

Highlights

Alzheimer’s disease (AD) is a degenerative disorder of the human central nervous system (CNS)
Observations on the physiological processing of amyloid protein precursor (APP) and on the effects of pathogenic mutations in the APP and/or the presenilin genes have led to the hypothesis that aberrant processing of APP into amyloid-β peptide (Aβ) peptides is linked to AD [3]
We demonstrated the effects of SOFAHDV Rz targeting APP mRNA on Aβ production

Summary

Introduction

Alzheimer’s disease (AD) is a degenerative disorder of the human central nervous system (CNS). The ε4 allele of apolipoprotein E, a strong genetic risk factor for the development of AD, has been linked to either enhancing Aβ aggregation or decreasing its clearance in brain tissue [5, 6] These observations strongly suggest that targeting Aβ metabolism is a worthwhile therapeutic approach and that reducing its level in the brain may block both the neurodegenerative process and cognitive decline. A novel targetdependent ribozyme that increases HDV Rz fidelity was engineered [9] This new ribozyme possesses a module (the SOFA, for Specific On/Off Adaptor) that switches the cleavage activity from Off to On when in the presence of the appropriate substrate (Figure 1). We demonstrated the effects of SOFAHDV Rz targeting APP mRNA on Aβ production

Experimental Procedures

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Results

Discussion