Affiliations: [a] Department of Neuroscience and Center for Neurovirology, Temple University School of Medicine, Philadelphia, PA, USA | [b] Kinsmen Laboratory of Neurological Research, University of British Columbia, Vancouver, BC, Canada
Correspondence:
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Corresponding author: Kamel Khalili, Ph.D., Department of Neuroscience, Center for Neurovirology, Temple University School of Medicine, 1900 North 12th Street, Philadelphia, PA 19122, USA. Tel.: +1 215 204 0678; Fax: +1 215 204 0679; E-mail: kamel.khalili@temple.edu.
Note: [1] The first two authors contributed equally to this work.
Abstract: 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-β protein precursor (AβPP) is a developmentally regulated protein which promotes neuronal survival. Both the human and mouse AβPP promoters contain multiple G/C rich sequences which regulate AβPP at the transcriptional and translational levels. Using an in vitro reporter assay, we confirmed that Pur-alpha consensus binding sites within the human AβPP promoter down-regulate AβPP transcription. Electrophoretic mobility shift and chromatin immunoprecipitation assays (ChIP) showed direct binding of Pur-alpha to the AβPP promoter. Down regulation of AβPP went beyond the transcriptional level as overexpression of Pur-alpha in glial and fibroblast cell lines decreased basal levels of AβPP while siRNA targeting Pur-alpha increased basal levels of AβPP. 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 AβPP levels by the transcriptional regulatory protein, Pur-alpha, and suggest that Pur-alpha may be involved in the dysregulation of AβPP in Alzheimer's disease.
