Role of caspase-12 in amyloid β-peptide-induced toxicity in organotypic hippocampal slices cultured for long periods

Abstract

Amyloid β (Aβ) toxicity has been implicated in cell death in the hippocampus, but its specific mechanisms are poorly understood. In this study, Aβ-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 Aβ25-35 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 Aβ25-35. 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 Aβ25-35-induced toxicity. The immunoreactivity of cleaved caspase-12 was increased whereas that of glucose-regulated protein 78 was not altered after exposure to Aβ25-35. 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 Aβ-induced toxicity and that the Aβ-induced cell death involves caspase-12-dependent pathways. It is also suggested that SAC is able to protect against the Aβ-induced neuronal cell death through the inhibition of the caspase-12-dependent pathway. ©2007 The Japanese Pharmacological Society.