Thursday, January 10, 2013


       Like the use of protease inhibitors to limit APP cleavage, drug-induced down-regulation of APP-gene transcriptional control has the intrinsic problem that DNA motifs are shared with several other genes. Certainly targeting the DNA promoter sites in front of the APP gene as a therapeutic strategy for AD has the disadvantage that several genes share the common enhancer sequences that control APP gene expression. As an example, NFkB is a well-characterized transcription enhancer that controls immunoglobulin gene expression, in addition to APP gene expression, in response to inflammatory signals.

    AP-1 sites are palindromes in front of the APP gene, which bind the cJun/cFos proto-oncogenes during stress, but the presence of this site in the enhancers of several other stress-responsive genes precludes the use of this site as a therapeutic target for AD. These considerations imply that new DNA-targeting drugs will not only suppress the gene of interest (e.g., APP for AD), but will also interfere with the expression of related and essential housekeeping genes, resulting in unwanted metabolic side effects. Despite these difficulties, companies such as Abbott Laboratories  and Hoechst Marion Roussel (Ringheim et al., 1998) have explored the potential
to modulate APP gene transcription.

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