Caspase inhibition attenuates accumulation of beta-amyloid by reducing beta-secretase production and activity in rat brains after stroke.
In this study, we tested if caspase-3 inhibition decreased ischemia-induced Abeta elevation by reducing beta-secretase (BACE1) activity. Changes in caspase-3, Abeta and BACE1 levels were detected in rat striatum on different days after middle cerebral artery occlusion using immunostaining. We found that the positive labeled cells of activated caspase-3, Abeta, and BACE1 were significantly and time-dependently increased in the ipsilateral striatum. The results of Western blotting and RT-PCR showed that caspase-3 inhibitor Z-DEVD-FMK reduced BACE1 mRNA and protein levels, and inhibited its protease activity, thereby decreasing the amount of APP C99 and Abeta in ischemic brains. Moreover, Z-DEVD-FMK reduced BACE1 and GFAP double-labeled cells, but not GFAP protein levels or GFAP-labeled cells, in the ipsilateral striatum. Thus, we demonstrated that caspase-3 inhibition attenuated ischemia-induced Abeta formation by reducing BACE1 production and activity. This finding provides a therapeutic strategy for preventing Abeta accumulation and reducing the risk of neurodegeneration after stroke.
Xiong
Man
M
Department of Neurobiology, Institute of Biomedical Sciences, State Key Laboratory of Medical Neurobiology, Shanghai Medical College of Fudan University, Shanghai, PR China.
Zhang
Ting
T
Zhang
Lin-Mei
LM
Lu
Shi-De
SD
Huang
Ya-Lin
YL
Sun
Feng-Yan
FY
D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism*; D015153:Blotting, Western; D002545:Brain Ischemia / Q000378:metabolism* / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D061945:Caspase Inhibitors; D003342:Corpus Striatum / Q000378:metabolism* / Q000473:pathology; D015870:Gene Expression; D007150:Immunohistochemistry; D020244:Infarction, Middle Cerebral Artery; D008297:Male; D018613:Microscopy, Confocal; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009842:Oligopeptides / Q000378:metabolism / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction
D016229:Amyloid beta-Peptides; D061945:Caspase Inhibitors; D009419:Nerve Tissue Proteins; D009842:Oligopeptides; D011480:Protease Inhibitors; D012333:RNA, Messenger; C110772:benzoylcarbonyl-aspartyl-glutamyl-valyl-aspartyl-fluoromethyl ketone; D053829:Amyloid Precursor Protein Secretases; D053148:Caspase 3; D016282:Aspartic Acid Endopeptidases; C509281:Bace1 protein, rat