MRNA expression and activity of ADAM17 in hippocampus after chronic cerebral hypoperfusion: experiment with aged rats

Abstract

To explore the effect of alpha-secretase on the pathogenesis of cognitive impairment following cerebral ischemia. Forty-eight 12~16-months-old Wistar rats were randomly divided into 2 equal groups: hypoperfusion group, undergoing permanent occlusion of bilateral common carotid arteries to mimic cerebral hypoperfusion, and sham-operation group. Each group was further divided into 1, 2, 4, and 16 week subgroups. Y-maze test was conducted before operation and at different time points as mentioned above to examine the spatial learning and memory ability. The rats tested by Y-maze were killed with their hippoccampi taken out. Realtime PCR was used to assay the mRNA expression of a disintegrin and metalloproteinase (ADAM)-17 representing alpha-secretase in the hippocampus, and fluorescence spectrometry was applied to measure activity thereof. The numbers of electric stroke since 2 weeks after hypoperfusion were significantly higher than that before hypoperfusion in the same group and those of the sham-operation group (P < 0.05 or P < 0.01). The mRNA expressions of hippocampal ADAM17 of the hypoperfusion subgroup 2, 4, and 16 weeks after operation were 0.78 +/- 0.03, 0.78 +/- 0.02, and 0.54 +/- 0.03 respectively, all significantly lower than those of the sham-operation group (1.12 +/- 0.05, 0.99 +/- 0.04, and 1.01 +/- 0.04 respectively, all P < 0.01). The average fluorescence values of hippocampal alpha-secretase 1, 2, 4, and 16 weeks after hypoperfusion of the hypoperfusion group were 33,880 +/- 1086, 37,496 +/- 817, 32,295 +/- 864 and 30,069 +/- 1111, respectively, all significantly lower than those of the sham-operation group (39 497 +/- 838, 39 802 +/- 1052, 40,137 +/- 776, and 39,894 +/- 1076 respectively, all P < 0.01). The mRNA expression of ADAM17 that represents alpha-secretase in the hippocampus is down-regulated and the activity of alpha-secretase is decreased after chronic cerebral hypoperfusion. That may subsequently result in accumulation of beta amyloid precursor protein, substrate of alpha-secretase, (APP), and then activate the other pathway cleaving APP, i.e., the pathway by beta secretase. At last, the production of beta amyloid protein in brain after chronic cerebral hypoperfusion increases and impairs the memory.