Presenilin-1 mutation activates the signaling pathway of caspase-4 in endoplasmic reticulum stress-induced apoptosis.
In the previous reports, we showed that the familial Alzheimer's disease (AD)-linked presenilin-1 (PS1) mutation induced the fragility to the endoplasmic reticulum (ER) stress and that caspase-4 mediates ER stress-induced- and beta-amyloid induced-apoptotic signaling in human cells. These results suggest the involvement of ER stress and caspase-4 in the cell death observed in AD. In this report, we studied the activation of caspase-4 in the familial AD-linked PS1 mutation (DeltaE9). Cleavage of caspase-4 under ER stress was enhanced by the overexpression of the familial AD-linked mutation (DeltaE9), showing that caspase-4 is a key caspase involved in the apoptotic signaling of AD. We also showed that the overexpression of caspase-4 induced cleavage of caspase-9 and caspase-3 without releasing cytochrome-c from the mitochondria. Thus, caspase-4 activates downstream caspases independently of mitochondrial apoptotic signaling and this might contribute to the pathogenesis of AD. To sum up our data, the familial AD-linked PS1 mutation accelerates the cleavage of caspase-4 under the ER stress and results in the activation of caspase-9 and caspase-3, apoptosis signal, without releasing cytochrome-c.
Yukioka
Futoshi
F
Department of Anatomy and Neuroscience, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
Matsuzaki
Shinsuke
S
Kawamoto
Keisuke
K
Koyama
Yoshihisa
Y
Hitomi
Junichi
J
Katayama
Taiichi
T
Tohyama
Masaya
M
D000199:Actins / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D015153:Blotting, Western; D019556:COS Cells; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D053471:Caspases, Initiator / Q000096:biosynthesis* / Q000235:genetics; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D045304:Cytochromes c / Q000378:metabolism / Q000502:physiology; D004721:Endoplasmic Reticulum / Q000201:enzymology*; D004789:Enzyme Activation / Q000502:physiology; D006801:Humans; D009154:Mutation / Q000502:physiology; D053764:Presenilin-1 / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D013312:Stress, Physiological / Q000503:physiopathology; D013347:Subcellular Fractions / Q000378:metabolism
D000199:Actins; D053764:Presenilin-1; D045304:Cytochromes c; C093516:CASP4 protein, human; D053148:Caspase 3; D053453:Caspase 9; D053471:Caspases, Initiator