Involvement of calcium ions in amyloid-β-induced lamin fragmentation

Abstract

Amyloid-β (Aβ) peptide, the main pathogenic peptide in Alzheimer's disease, has been shown to induce an increase in cytoplasmic calcium concentration (CCC). In the current study, we explored the cytotoxic signal transduction pathway in 42-amino-acid Aβ (Aβ42)-treated HeLa cells in relation to the increase in CCC. The increase in CCC was prominent in cells treated twice with oligomeric Aβ42. We previously showed that double treatment also promoted Aβ-induced lamin fragmentation (AILF), which appears to be mediated by cathepsin L. Apoptotic caspase activation was a downstream event of AILF. The Ca²⁺ chelator BAPTA-AM suppressed cell death, cathepsin L activation, AILF, and caspase activation in Aβ-treated cells. These results indicate that Aβ42 induces an increase in CCC, which is an event upstream of the cytotoxic processes. The products of AILF are different from those produced by other cell death-inducing agents, such as staurosporine, which induces caspase-6-mediated lamin fragmentation (CMLF). CMLF was unaffected by BAPTA-AM and was not detected in cells treated with Aβ42, indicating that Aβ42 peptide induced a specific cytotoxic pathway involving AILF via increased CCC. We confirmed that the same processes (except caspase activation) operated in Aβ42-treated neuroblastoma SH-SY5Y cells.

Keywords: Alzheimer's disease; Amyloid β; Calcium; Caspase; Cathepsin L; Lamin.