Sp1 and Smad transcription factors co-operate to mediate TGF-β-dependent activation of amyloid-β precursor protein gene transcription

Abnormal deposition of Aβ (amyloid-β peptide) is one of the hallmarks of AD (Alzheimer's disease). This peptide results from the processing and cleavage of its precursor protein, APP (amyloid-β precursor protein). We have demonstrated previously that TGF-β (transforming growth factor-β), which is overexpressed in AD patients, is capable of enhancing the synthesis of APP by astrocytes by a transcriptional mechanism leading to the accumulation of Aβ. In the present study, we aimed at further characterization of the molecular mechanisms sustaining this TGF-β-dependent transcriptional activity. We report the following findings: first, TGF-β is capable of inducing the transcriptional activity of a reporter gene construct corresponding to the + 54/ + 74 region of the APP promoter, named APP^TRE (APP TGF-β-responsive element); secondly, although this effect is mediated by a transduction pathway involving Smad3 (signalling mother against decapentaplegic peptide 3) and Smad4, Smad2 or other Smads failed to induce the activity of APP^TRE. We also observed that the APP^TRE sequence not only responds to the Smad3 transcription factor, but also the Sp1 (signal protein 1) transcription factor co-operates with Smads to potentiate the TGF-β-dependent activation of APP. TGF-β signalling induces the formation of nuclear complexes composed of Sp1, Smad3 and Smad4. Overall, the present study gives new insights for a better understanding of the fine molecular mechanisms occurring at the transcriptional level and regulating TGF-β-dependent transcription. In the context of AD, our results provide additional evidence for a key role for TGF-β in the regulation of Aβ production.