The Effect of Stepwise Cerebral Hypoperfusion on Energy Metabolism and Amyloid Precursor Protein (APP) in Cerebral Cortex and Hippocampus in the Adult Rat

Abstract

To study the relationship between cerebral blood flow, energy metabolism, and the formation of amyloid precursor protein (APP), an in vivo animal model was established in which stepwise long-term cerebral hypoperfusion states were induced. Adult rats underwent a stepwise chronic cerebral hypoperfusion by crosswise occlusion of the carotid and vertebral arteries with different periods and severity of hypoperfusion until the final steady-state experiment. Investigations of metabolic compounds were done in hippocampus and parietotemporal cerebral cortex. The analysis of energy-rich phosphates and adenosine was examined by HPLC analysis. Substrate concentrations of pyruvate and lactate were measured spectrophotometrically. The APP holoprotein was investigated by immunblot technique. Long-term cerebral hypoperfusion induced a decrease of energy-rich phosphates in the brain areas studied, whereas the concentration of adenosine and the ATP turnover were increased. Pyruvate decreased, and lactate was increased, pointing to a shift in the cytoplasmatic redox state. More severe changes were found in parietotemporal cerebral cortex in comparison to the hippocampus. After 2-vessel occlusion, the concentration of APP decreased, whereas the APP concentration was significantly increased in rat brain after 4-vessel occlusion. It has been demonstrated for the first time in vivo that the reduction in cerebral energy metabolism alters the formation of APP due to cerebral hypoperfusion.