Role of caspase-3 in regulation of the amyloid-degrading neuropeptidase neprilysin level in the rat cortex after hypoxia

Abstract

Analysis of the effect of a caspase-3 inhibitor on the level of amyloid-degrading neuropeptidase neprilysin (NEP) in the cortex of rats exposed to prenatal hypoxia (7% О2, 3 h) on day 14 of embryonic development (E14) was performed. It was found that rats exposed to prenatal hypoxia on days 20–30 after birth had an increased level and activity of caspase-3 with reduced levels of NEP and the C-terminal fragment of the amyloid precursor protein intracellular domain (AICD) which regulates NEP expression. In hypoxic animals 3 days after a single intraventricular injection of a caspase inhibitor (Ac-DEVD-CHO) on P20, the AICD and NEP levels were found to be increased up to the levels observed in control rats. The results suggest that the increase in caspase-3 enzyme activity could affect NEP expression via proteolytic degradation of its transcription factor AICD. These findings represent the first demonstration of the role of caspases in AICD-dependent regulation of NEP production in the brain of mammals under hypoxic conditions.