Abstract:OBJECTIVE: β-amyloid precursor protein (β-APP) is thought to be a sensitive marker for brain white matter damage (WMD) and participates in the mechanisms of hypoxic-ischemic brain damage. This paper aims to study the influence of ischemia and IGF-1 treatment on the expression of β-APP in white matter of near-term fetal sheep. METHODS: Romney-Suffolk fetal sheep were instrumented at 117 to 124 days of gestation (term=147 days). Reversible cerebral ischemia was induced by occlusion of bilateral carotid arteries for 30 mins. After damage the sheep were randomly divided into two groups: the Ischemic group (n=8) and the IGF-1 treatment group (Treatment group, n=9). The sham-operation group (n=5) was used as Control group. In the Treatment group, 3 μg (1 ml) recombinant human IGF-1 (rhIGF-1) was infused into the left lateral ventricle, 90 mins after reperfusion. The Control group received infusion of 1 ml artificial cerebrospinal fluid into the left ventricle. Ninety-six hrs after ischemia, the sheep were sacrificed and the brains were fixed. Immunohistochemical staining was performed to assess glial fibrillary acidic protein (GFAP), β-APP positive cells and the myelin basic protein (MBP) density in the white matter. Fluorescent staining was performed for double labeling. RESULTS: The MBP density of the Ischemic group ( 4.7± 7.1) was significantly reduced as compared with the Control group ( 27.8± 4.8, P< 0.001). β-APP positive cells were not observed in the Control group. β-APP positive cells of the Ischemic group increased significantly after ischemia ( 49.6± 23.7, P< 0.001). IGF treatment significantly reduced the β-APP positive cells ( 17.9± 16.5, P< 0.01). Fluorescent double labeling showed that the β-APP positive cells were co-localized with GFAP positive cells. CONCLUSIONS: Ischemia increases the expression of β-APP by astrocytes in near-term fetal sheep white matter, which may underlie the mechanisms of ischemic WMD. IGF-1can reduce the expression of β-APP, which may be mechanism of its protective effect against WMD.
