Expression of amyloid precursor protein (β‐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.

Comparative SAGE analysis of the response to hypoxia in human pulmonary and aortic endothelial cells

“…These changes were statistically significant. In contrast, in our previous analysis of the hypoxia-responsive transcriptome in HAECs (40), we did not find these genes to be significantly altered, although BACE2 was upregulated at 24 h. Numerous reports (3,39) have linked the expression of Alzheimer's disease-associated genes with hypoxia and ischemia, but these observations have almost exclusively been made in neuronal tissue.…”

Effects of Hypoxia and Oxidative Stress on Expression of Neprilysin in Human Neuroblastoma Cells and Rat Cortical Neurones and Astrocytes

“…To study the effect of hypoxia on expression and localisation of proteins of interest, NB7 cells or rat primary neurones and astrocytes were incubated in an O 2 /CO 2 incubator (MC0-175M, Sanyo) for 24 h under 2.5 % or 1% O 2 depending on the conditions of the experiments and in accordance with previous reports [6]. To induce oxidative stress in the NB7 cells, H 2 O 2 (Sigma-Aldrich Co., Poole, Dorset, UK) to a final concentration of 40 lM was added to the culture medium and the cells were kept in an incubator under normoxic conditions.…”

“…Metabolism of the Alzheimer's amyloid b-peptide (Ab) is affected by ischemia and hypoxia and an increased level of the amyloid precursor protein (APP) is a part of the acute adaptive response of the brain to hypoxia [6]. In cell models chronic hypoxia was shown to alter processing of APP and a decrease in expression of ADAM10 possessing a-secretase activity [7,8].…”

Insulin-Degrading Enzyme Sorting in Exosomes: A Secretory Pathway for a Key Brain Amyloid-β Degrading Protease

“…Interestingly, hypoxia was suggested to be linked with AD pathogenesis [27] since the metabolism of the Aβ is affected as a consequence of its over-production mediated by increased BACE expression [28] and γ-secretase activity [29]. This mechanism was considered part of the acute adaptive response of the brain to hypoxia [30] to restrict the progression of neurodegeneration.…”