Expression of amyloid precursor protein (beta-APP) in the neonatal brain following hypoxic ischaemic injury.

Abstract

Perinatal hypoxic ischaemic brain injury (HII) is a major cause of neonatal mortality and long-term neurological morbidity. An understanding of the molecular events which follow HII may lead to novel treatments to improve the final outcome for affected infants. The beta-amyloid precursor protein (beta-APP) is a widely expressed transmembrane protein whose proposed functions include stabilization of neuronal calcium fluxes, inhibition of the clotting cascade and cell-cell or cell-matrix adhesion. Normally present at low levels in neurons its expression is induced as part of the acute response of the adult brain to HII. This study aimed to determine whether beta-APP is also part of the acute adaptive response of the infant brain to HII. Immunohistochemistry and Western blotting were used to assess cerebral beta-APP expression in 14-day-old rat pups subjected to unilateral HII, and in 10 term human infants, who died between 12 h and 16 months after severe perinatal HII. In the rat pups beta-APP expression was increased by 2 h post-injury, peaked, fourfold above control levels, at 24 h and gradually declined over the following 4 days. Expression was induced bilaterally, but was greater on the side of injury. In the human infants, increased, predominantly neuronal expression of beta-APP, was detectable immunohistochemically within 24 h of injury and was greatest in those infants dying within 3 days. Expression was particularly strong in the areas showing histological evidence of injury, but was also seen in apparently undamaged areas. We conclude that beta-APP induction is part of the the acute adaptive response of the neonatal brain to HII.