Amyloid precursor protein mRNA 5'-untranslated region iron-responsive element (APP 5'-UTR IRE) (APP 5'-UTR IRE)

The Amyloid precursor protein (APP) mRNA 5'-untranslated region (5'-UTR) contains a functional iron-responsive element (IRE) that post-transcriptionally regulates APP synthesis in response to intracellular iron levels (Rogers et al., 2002). This stem-loop structure is a binding site for Iron Regulatory Proteins (IRP1 and IRP2), which act as translational repressors when iron levels are low. In the presence of high iron, IRPs dissociate, allowing for the translation of APP, which has been linked to the pathogenesis of Alzheimer's disease through the subsequent production of neurotoxic amyloid-beta (Aβ) peptides (Cho et al., 2010). Therapeutic strategies targeting this IRE aim to use small molecules to stabilize the IRP-IRE interaction or directly inhibit translation, thereby reducing the total pool of APP available for amyloidogenic processing. This approach is distinct from secretase inhibition as it targets the protein production stage rather than the cleavage stage. Clinical candidates like Posiphen have demonstrated the ability to lower Aβ and tau levels by interacting with this regulatory RNA element (Bandyopadhyay et al., 2013).

Other names

APP IREAmyloid precursor protein iron-responsive elementAPP 5'UTR stem-loopAPP 5'-UTR IRE

Small molecule binding to the IRE stem-loop or stabilization of the Iron Regulatory Protein (IRP) complex to inhibit the translation of APP mRNA, thereby reducing the production of amyloid precursor protein and its neurotoxic cleavage products (Rogers et al., 2002; Bandyopadhyay et al., 2013).