Aβ 17-42 in Alzheimer's disease activates JNK and caspase-8 leading to neuronal apoptosis

Wanli Wei, Darrell D. Norton, Xiantao Wang, John W. Kusiak

Research output: Contribution to journalArticlepeer-review

114 Scopus citations


The p3 peptide [amyloid β-peptide (Aβ) 17-40/42], derived by α- and γ-secretase cleavage of the amyloid precursor protein (APP), is a major constituent of diffuse plaques in Alzheimer's disease and cerebellar preamyloid 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 Aβ 17-42 leads to apoptosis in two human neuroblastoma cell lines, SH-SY5Y and IMR-32. Aβ 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 Aβ 17-42-induced neuronal death. Aβ 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 Aβ 17-42 induced neuronal death. These results demonstrate that Aβ 17-42 induced neuronal apoptosis via a Fas-like/caspase-8 activation pathway. Our findings reveal the previously unrecognized toxic effect of Aβ 17-42. We propose that Aβ 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.

Original languageEnglish (US)
Pages (from-to)2036-2043
Number of pages8
Issue number9
StatePublished - Sep 2002
Externally publishedYes


  • Alzheimer's disease
  • Apoptosis
  • Caspase
  • JNK
  • p3 peptide

ASJC Scopus subject areas

  • Clinical Neurology


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