Role of caspase-12 in amyloid beta-peptide-induced toxicity in organotypic hippocampal slices cultured for long periods.
Amyloid beta (Abeta) toxicity has been implicated in cell death in the hippocampus, but its specific mechanisms are poorly understood. In this study, Abeta-induced cell death was investigated in organotypic hippocampal slice cultures (OHCs) that were cultured for various periods in vitro. There were no obvious histological differences among slices cultured for 3 to 7 weeks in vitro. Although there was little neurotoxicity after treatment with Abeta25-35 in OHCs cultured for relatively shorter periods (3-5 weeks), age-dependent cell death was evident in OHCs cultured for relatively longer periods (6-7 weeks) after exposure to Abeta25-35. In OHCs cultured for 7 weeks, S-allyl-L-cysteine (SAC), a component of aged garlic extract, protected the cells in areas CA1 and CA3 and the dentate gyrus from Abeta25-35-induced toxicity. The immunoreactivity of cleaved caspase-12 was increased whereas that of glucose-regulated protein 78 was not altered after exposure to Abeta25-35. The increases in the cleaved caspase-12 were also reversed by simultaneously applied SAC. These results suggest that OHCs cultured for relatively longer periods are more susceptible to Abeta-induced toxicity and that the Abeta-induced cell death involves caspase-12-dependent pathways. It is also suggested that SAC is able to protect against the Abeta-induced neuronal cell death through the inhibition of the caspase-12-dependent pathway.
Ishige
Kumiko
K
Research Unit of Pharmacology, College of Pharmacy, Nihon University, Funabashi, Japan.
Takagi
Noritaka
N
Imai
Toru
T
Rausch
Wolf Dieter
WD
Kosuge
Yasuhiro
Y
Kihara
Tetsuroh
T
Kusama-Eguchi
Kuniko
K
Ikeda
Hiroko
H
Cools
Alexander Rudolf
AR
Waddington
John Lionel
JL
Koshikawa
Noriaki
N
Ito
Yoshihisa
Y
D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D015153:Blotting, Western; D053454:Caspase 12 / Q000378:metabolism* / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects; D003545:Cysteine / Q000031:analogs & derivatives / Q000494:pharmacology; D018891:Dentate Gyrus / Q000187:drug effects* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000201:enzymology; D000091342:Endoplasmic Reticulum Chaperone BiP; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D006360:Heat-Shock Proteins / Q000378:metabolism; D007051:Ibotenic Acid / Q000494:pharmacology; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D018832:Molecular Chaperones / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D009924:Organ Culture Techniques; D010446:Peptide Fragments / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
D016229:Amyloid beta-Peptides; D000091342:Endoplasmic Reticulum Chaperone BiP; D018690:Excitatory Amino Acid Agonists; C051684:GRP78 protein, rat; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D010446:Peptide Fragments; C074636:amyloid beta-protein (25-35); C113041:amyloid beta-protein (35-25); D007051:Ibotenic Acid; C065299:S-allylcysteine; D007770:L-Lactate Dehydrogenase; D053454:Caspase 12; D003545:Cysteine