Modulation of neutrophil apoptosis by β-amyloid proteins

This study examined the effect of amyloid β peptide (Aβ) and the secretase inhibitors of amyloid precursor proteins (APP) on the spontaneous apoptosis of neutrophils. Aβ(1-40) decreased the apoptotic rate of neutrophils. The delayed apoptosis by Aβ was not blocked by pertussis toxin and N-formyl peptide receptor-like 1 antagonistic peptide, WRWWWW. The inhibitors of phoshoinositide 3-kinase (LY294002), phospholipase C (U73122), or Ca++-dependent protein kinase C (Go6976) abrogated the anti-apoptotic effect of Aβ on neutrophils. Moreover, the Aβ-induced delay of apoptosis was inhibited by a calcium chelator, BAPTA/AM. The amount of the APP protein was reduced in the cultured neutrophils and the APP level in the Aβ or pancaspase-treated neutrophils was lower than that in the cultured neutrophils. However, the reduction in APP level was recovered after treating them with the secretase inhibitors or anti-Fas antibody. The exogenous addition of cell permeable β- and γ-secretase inhibitors resulted in an increase in the rate of the apoptosis. The regulation of neutrophil apoptosis by the addition of Aβ and secretase inhibitors occurred via the caspase -8, -9, -3, and mitochondrial-dependent pathways. This suggests that the intracellular β-amyloid proteins play a role as regulating factor of neutrophil survival and that Aβ-induced delay of apoptosis is mediated by other receptors rather than a seven-transmembrane G protein-coupled receptor(s).