Figure 10.

Model of Antagonistic PuF vs. SP1 regulation of the APP gene and disruption in AD. A. Non-pathogenic APP expression, levels regulated by PuF. In normal brain, PuF would compete with SP1 at the PRE and result in normal levels of APP mRNA and protein. Aβ would be restricted to non-pathogenic concentrations. B. Pathogenic APP expression resulting from disruption of PuF regulation of the PRE. Disruption of the PRE, such as through environmentally induced DNA oxidation at GG dimers, “*”, may reduce affinity of the PRE for PuF more severely than for SP1. Effective SP1 activity then serves to upregulate APP expression levels beyond a pathogenic threshold.