The nucleic acid binding protein, Pur-alpha, is best characterized as a transcription factor with affinity to single stranded G/C rich regions. Pur-alpha exhibits developmental and tissue-specific regulation and plays a critical role in neuronal development and differentiation. Similar to Pur-alpha, the amyloid-beta protein precursor (AbetaPP) is a developmentally regulated protein which promotes neuronal survival. Both the human and mouse AbetaPP promoters contain multiple G/C rich sequences which regulate AbetaPP at the transcriptional and translational levels. Using an in vitro reporter assay, we confirmed that Pur-alpha consensus binding sites within the human AbetaPP promoter down-regulate AbetaPP transcription. Electrophoretic mobility shift and chromatin immunoprecipitation assays (ChIP) showed direct binding of Pur-alpha to the AbetaPP promoter. Down regulation of AbetaPP went beyond the transcriptional level as overexpression of Pur-alpha in glial and fibroblast cell lines decreased basal levels of AbetaPP while siRNA targeting Pur-alpha increased basal levels of AbetaPP. Similar findings were observed in brain tissue and fibroblasts from mice with targeted deletion of Pur-alpha. These data point to a novel mechanism of controlling AbetaPP levels by the transcriptional regulatory protein, Pur-alpha, and suggest that Pur-alpha may be involved in the dysregulation of AbetaPP in Alzheimer's disease.