Focal cerebral ischemia in rats alters APP processing and expression of Aβ peptide degrading enzymes in the thalamus

Abstract

We have previously demonstrated aggregation of amyloid precursor protein (APP) and β-amyloid (Aβ) to dense plaque-like deposits in the thalamus of rats subjected to transient middle cerebral artery occlusion (MCAO). Here, we investigated the underlying molecular effects of MCAO on APP processing and expression profiles of Aβ degrading enzymes in the cortex adjacent to the infarct (penumbra) and ipsilateral thalamus 2, 7 and 30 days after ischemic insult. Enhanced β-amyloidogenic processing of APP and altered insulin degrading enzyme and neprilysin expression were observed in the thalamus, but not the penumbral cortex, 7 and 30 days after MCAO coinciding with increased calcium levels and β-secretase (BACE) activity. Consecutively, increased BACE activity associated with depletion of BACE trafficking protein GGA3, suggesting a post-translational stabilization of BACE. These results demonstrate that focal cerebral ischemia leads to complex pathogenic events in the thalamus long after the initial insult.

Keywords

• Aβ-peptide
• Alzheimer's disease
• β-secretase
• Calcium
• Golgi-localized γ-ear-containing ARF binding protein
• Insulin degrading enzyme