Presenilin-2 (PS2) expression up-regulation in a model of retinopathy of prematurity and pathoangiogenesis

Presenilin-2 (PS2; AD4), a regulator of intercellular signaling during CNS development and cell fate determination, appears to be involved in pathogenic processing of beta-amyloid precursor protein (betaAPP) into potentially neurotoxic beta-amyloid (Abeta) peptides. The PS2 gene promoter contains multiple DNA binding sites for the relatively rare hypoxia-inducible transcription factor HIF-1, suggesting that PS2 expression may be a sensitive indicator of decreased oxygen availability. We have used a cycled hypoxia/hyperoxia (10-50% O2) protocol followed by normoxia (20% O2) as a retinal model of retinopathy of prematurity to induce neovascularization (NV) in rat pups. Retinal cell nuclear extracts from pups undergoing hypoxia exhibited a dramatic increase in HIF-1-DNA binding, followed by a delayed (2-7 day) elevation of PS2 RNA message and protein. PS2 gene activation during hypoxia may direct cellular fate towards pathoangiogenesis and intercellular PS2-mediated signaling dysfunction.