β-Amyloid Precursor Protein and β-Amyloid Peptide Immunoreactivity in the Rat Brain After Middle Cerebral Artery Occlusion

Abstract

Background and Purpose-Previous studies have shown that the ␤-amyloid precursor protein (␤APP) is upregulated after cerebral ischemia and that the ␤-amyloid (A␤) fragment may be toxic to brain cells. Although stroke in humans usually afflicts the elderly, most experimental studies on the nature of cerebral ischemia have used young animals. To test the hypothesis that the upregulation and/or persistence of amyloidogenic proteins is exacerbated in aged rats after cerebral ischemic stroke, we studied the expression of ␤APP and its proteolytic product A␤ in the brains of young and old rats 7 days after temporary cerebral ischemia. Methods-Focal cerebral ischemia was produced by reversible occlusion of the right middle cerebral artery in 3-and 20-month-old male Sprague-Dawley rats. After 1 week, brains were removed and immunostaining was performed for ␤APP, A␤, and ED1 for macrophages and glial fibrillary acidic protein (GFAP). Results-Histological staining revealed that the degree of necrotic cavitation in the infarct core was relatively less in aged rats than in young rats, suggesting a slower pace of degenerative change and/or tissue removal in older animals. ␤APP immunoreactivity was robustly increased, primarily in macrophage-like, ED1-positive cells in the infarct core and in the penumbra of both young and aged animals. A␤ immunoreactivity was evident in GFAP-positive astrocytic somata and processes, and also in clusters of small spherical structures in the penumbra. These A␤-immunoreactive minispheres were more numerous in aged rats than in young rats. Conclusions-The presence of ␤APP and A␤ immunoreactivity in the infarct core and penumbra indicates that cerebral ischemia promotes conditions that are favorable to the focal accumulation of ␤APP and its proteolytic fragments, especially in the aged brain. (Stroke. 1998;29:2196-2202.)

Down-regulation of parkin protein in transient focal cerebral ischemia: A link between stroke and degenerative disease?

“…First, diminished or impaired cerebral perfusion is a risk factor for Alzheimer's disease (31)(32)(33); second, in animals expressing mutant presenilin-1, the extent of brain injury induced by focal ischemia and the behavioral outcome is worsened (34); and third, transient ischemia induces ␤-amyloid peptide formation (35,36). The observation that ubiquitylated protein aggregates, characteristic features of degenerative diseases (37), are also found in acute pathological states of the brain such as stroke (15) further corroborates the notion that common denominators for cell injury exist in acute and degenerative diseases of the brain (6, 7).…”

Expression of Human Amyloid Precursor Protein in Rat Cortical Neurons Inhibits Calcium Oscillations

“…Neuronal injuries such as ischemia (Tomimoto et al, 1995;Popa-Wagner et al, 1998;Shi et al, 2000;Hellweg et al, 2003), trauma (Dewji et al, 1995;Van Den Heuvel et al, 2000) or neuroinflammation (Ringheim et al, 1998) induce APP overexpression, and acute APP overexpression leads to synaptic depression via reduced levels of AMPA and NMDA receptors (Kamenetz et al, 2003;Almeida et al, 2005;Ting et al, 2007). In addition, APP gene duplication results in early onset AD with cerebral amyloid angiopathy (Sleegers et al, 2006;Rovelet-Lecrux et al, 2006), further indicating that increased APP expression is a risk factor for AD.…”

NMDA Receptor Activation Inhibits α-Secretase and Promotes Neuronal Amyloid-β Production

“…In addition, a recent study pointed out the transient upregulation of ␤-secretase BACE-1 [␤-site amyloid precursor protein (APP) cleaving enzyme] expression 24 -72 h after TBI, accompanied by an elevation of its activity detected 48 h after onset (Blasko et al, 2004). Although the overall understanding of the conditions that govern A␤ accumulation into the brain parenchyma has greatly improved, the molecular mechanism linking acute brain injury to an increased A␤ production remains to be established (Roberts et al, 1994;Saido et al, 1994;Popa-Wagner et al, 1998).…”