Differential involvement of caspase-6 in amyloid-β-induced fragmentation of lamin A and B

Abstract

Amyloid-β (Aβ), a peptide implicated in Alzheimer's disease, was shown to cause specific fragmentation of lamin proteins, which was mediated by an unidentified protease named nuclear scaffold protease (NSP) independently of caspase-6. Because caspase-6 is responsible for the fragmentation process in many other damage-induced apoptosis, here we further investigated possible involvement of caspase-6 in Aβ-induced lamin fragmentation under various conditions. We found that lamin A fragment generated by NSP (named fragment b) disappeared in cells incubated with Aβ42 for prolonged periods and this product was preserved by a caspase-6 inhibitor. Furthermore, caspase-6 could remove fragment b in nuclei isolated from Aβ42-treated cells (ANU). Lamin B in ANU was fragmented by caspase-6 only after treatment with an alkaline phosphatase. The caspase-mediated fragmentation of lamin B was also achieved with nuclei isolated from cells incubated with Aβ42 plus a Cdk5 inhibitor. The results indicate that Aβ42 induces NSP-mediated fragmentation of lamin A and the following removal process of fragment b by caspase-6 and an Aβ-induced phosphorylation prevents the fragmentation of lamin B by caspase-6. The pathway leading to lamin protein fragmentation in this investigation appears to be specific for Aβ and thus the data will provide novel insights into the toxicity of the peptide.

Keywords

• Amyloid β
• Alzheimer's disease
• Lamin
• Nuclear scaffold protease
• Caspase-6
• Phosphorylation