[mRNA expression and activity of ADAM17 in hippocampus after chronic cerebral hypoperfusion: experiment with aged rats].
OBJECTIVE
To explore the effect of alpha-secretase on the pathogenesis of cognitive impairment following cerebral ischemia.


METHODS
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.


RESULTS
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).


CONCLUSIONS
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.
Yan
Fu-Ling
FL
Department of Neurology, Huashan Hospital Affiliated to Fudan University, Shanghai, China.
Zhang
Jie
J
Guan
Xue-Neng
XN
Hong
Zhen
Z
D051722:ADAM Proteins / Q000235:genetics* / Q000378:metabolism; D000072198:ADAM17 Protein; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D000818:Animals; D002545:Brain Ischemia / Q000503:physiopathology*; D015870:Gene Expression; D006624:Hippocampus / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013050:Spectrometry, Fluorescence
D012333:RNA, Messenger; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606464:Adam17 protein, rat