Sphingomyelinase dependent apoptosis of dendritic cells following treatment with amyloid peptides

Amyloid peptides are formed during inflammation and modify the function of immune cells. The present study explored the effect of amyloid β-peptide (Aβ1–42) and islet amyloid polypeptide (IAPP) on bone marrow derived dendritic cells (DCs). DCs were treated with Aβ1–42 or IAPP with subsequent assessment of ceramide formation, caspase 8 and 3 activity, DNA fragmentation and phosphatidylserine exposure. In addition, TNFα secretion was assessed in lypopolysaccharide (LPS)-stimulated Aβ1–42- or IAPP-treated DCs. Within 24 h Aβ1–42 and IAPP triggered ceramide formation, caspase 8 and caspase 3 activation, DNA fragmentation and annexin V binding in DCs obtained from wild type mice, whereas in DCs from sphingomyelinase deficient (asm−/−) mice and in wild type DCs treated with sphingomyelinase inhibitor amitriptyline all these effects were strongly impaired. Moreover, ceramide formation was also reduced in wild type DCs in which acid sphingomyelinase (Asm) was silenced with Asm-targeted siRNA. Finally, Aβ1–42 and IAPP treatment was further followed by a decline of TNFα formation in wild type DCs. In conclusion, amyloid peptides induce DC apoptosis presumably through activation of acid sphingomyelinase resulting in production of ceramide.