A 17–42 in Alzheimer’s disease activates JNK and caspase-8 leading to neuronal apoptosis

Author： Wei W. Norton D.D. Wang X. Kusiak J.W.

ISSN： 1460-2156

Source： Brain, Vol.125, Iss.9, 2002-09, pp. : 2036-2043

Disclaimer: Any content in publications that violate the sovereignty, the constitution or regulations of the PRC is not accepted or approved by CNPIEC.

Previous Menu Next

Abstract

The p3 peptide [amyloid -peptide (A) 17–40/42], derived by α- and -secretase cleavage of the amyloid precursor protein (APP), is a major constituent of diffuse plaques in Alzheimer’s disease and cerebellar pre-amyloid in Down’s syndrome. However, the importance of p3 peptide accumulation in Alzheimer’s disease and its toxic properties is not clear. Here, we demonstrate that treatment of cells with A 17–42 leads to apoptosis in two human neuroblastoma cell lines, SH-SY5Y and IMR-32. A 17–42 activated caspase-8 and caspase-3, induced poly(ADP-ribose) polymerase cleavage, but did not activate caspase-9. Selective caspase-8 and caspase-3 inhibitors completely blocked A 17–42-induced neuronal death. A 17–42 moderately activated c-Jun N-terminal kinase (JNK); however, overexpression of a dominant-negative mutant of SEK1, the upstream kinase of JNK, protected against A 17–42 induced neuronal death. These results demonstrate that A 17–42 induced neuronal apoptosis via a Fas-like/caspase-8 activation pathway. Our findings reveal the previously unrecognized toxic effect of A 17–42. We propose that A 17–42 constitutes an additional toxic peptide derived from APP proteolysis and may thus contribute to the neuronal cell loss characteristic of Alzheimer’s disease.