%0 Journal Article
%T Silencing of Amyloid Precursor Protein Expression Using a New Engineered Delta Ribozyme
%A Manel Ben Aissa
%A Marie-Claude April
%A Lucien-Junior Bergeron
%A Jean-Pierre Perreault
%A Georges Levesque
%J International Journal of Alzheimer's Disease
%D 2012
%I Hindawi Publishing Corporation
%R 10.1155/2012/947147
%X Alzheimer's disease (AD) etiological studies suggest that an elevation in amyloid-¦Â peptides (A¦Â) 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¨C42 residue peptide (A¦Â40£¿42) derived from amyloid protein precursor (APP). Most likely, reducing A¦Â 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¦Â accumulation in the cells, we have selectively chosen to target the primary step in the A¦Â 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¦Â levels in neuronal cells. Our results could lay the groundwork for a new protective treatment for AD. 1. Introduction Alzheimer¡¯s disease (AD) is a degenerative disorder of the human central nervous system (CNS). Its clinical and neuropathological features are defined by a progressive loss of cognitive function and by the onset of a slowly progressive impairment of memory during mid- to late-adult life. The neuropathological hallmarks of AD include the accumulation and aggregation of amyloid-¦Â peptide (A¦Â), neurofibrillary tangles, astrocytic gliosis, and reductions in the numbers of both neurons and synapses in many areas of the brain, particularly in the cerebral cortex and hippocampus [1]. Strong evidence from multiple studies suggests that defects in A¦Â regulation are one of the central biochemical events leading to the development of AD [2]. The neurotoxic A¦Â fragment originates from the amyloid protein precursor (APP) following sequential cleavages by ¦Â (BACE) and ¦Ã-secretases (presenilin complex). Observations on the physiological processing of 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 A¦Â peptides is linked to AD [3]. We have previously reported strong evidence indicating that the amyloid cascade is an early and critical event in the neurodegeneration associated with AD. For example, cell lines and/or transgenic mice expressing mutant presenilin 1 (PS1), presenilin 2 (PS2), or APP exhibit an accelerated rate of neurotoxic A¦Â formation [4]. Thus, the three known genetic causes of familial AD affect A¦Â metabolism. Moreover, the ¦Å4 allele of apolipoprotein E, a
%U http://www.hindawi.com/journals/ijad/2012/947147/