Differential binding and activation of caspase-3 in cultured hippocampal neurons by assembly forms of Aβ1-42

Paul A. St. John

Research output: Contribution to journalArticlepeer-review

5 Scopus citations


Amyloid-β (Aβ) peptides, the primary constituents of amyloid plaques in the brain in Alzheimer's disease (AD), may cause AD, but how they do so is not clear. Aβ peptides spontaneously aggregate, or self-assemble, to generate several distinct macromolecular and morphological forms that can differ significantly in their effects on cells. We have compared different assembly forms of Aβ1-42 (Aβ42) for their ability to trigger apoptosis in cultured hippocampal neurons at a submicromolar concentration and for their binding to such neurons. Fibrillar Aβ42 caused both morphological changes indicative of apoptosis and specific activation of caspase-3, a characteristic marker of neurodegeneration in AD, in hippocampal neurons, whereas other preparations tested did not do so under the same conditions. More aggregated forms of Aβ42, including both fibrils and a mixture of assembly forms termed Aβ-derived diffusible ligands (ADDLs), bound to neurons much more extensively and at lower concentrations than preparations that contained smaller forms. Fibrillar Aβ42, in particular, bound to neurons at concentrations as low as 1 nM. Colocalization studies showed that fibrillar Aβ42 bound almost exclusively at nonsynaptic sites. These results show differences between assembly forms of Aβ42 in the ability to trigger apoptotic signaling in CNS neurons, and they directly demonstrate differences between assembly forms in the binding to CNS neurons, a possible first step in the pathogenesis of AD. These results suggest that fibrillar Aβ42 contributes to the pathogenesis of AD.

Original languageEnglish (US)
Pages (from-to)1205-1214
Number of pages10
JournalJournal of Neuroscience Research
Issue number6
StatePublished - May 1 2007


  • Alzheimer's disease
  • Apoptosis
  • Caspase-3
  • Fibril
  • Hippocampus
  • β-amyloid

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience


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