Differential binding and activation of caspase-3 in cultured hippocampal neurons by assembly forms of A beta 1-42.
Amyloid-beta (A beta) 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. A beta 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 A beta(1-42) (A beta 42) for their ability to trigger apoptosis in cultured hippocampal neurons at a submicromolar concentration and for their binding to such neurons. Fibrillar A beta 42 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 A beta 42, including both fibrils and a mixture of assembly forms termed A beta-derived diffusible ligands (ADDLs), bound to neurons much more extensively and at lower concentrations than preparations that contained smaller forms. Fibrillar A beta 42, in particular, bound to neurons at concentrations as low as 1 nM. Colocalization studies showed that fibrillar A beta 42 bound almost exclusively at nonsynaptic sites. These results show differences between assembly forms of A beta 42 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 A beta 42 contributes to the pathogenesis of AD.
St John
Paul A
PA
Department of Cell Biology and Anatomy, University of Arizona College of Medicine, Tucson, AZ 85724, USA. stjohn@u.arizona.edu
D016229:Amyloid beta-Peptides / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000648:ultrastructure; D000704:Analysis of Variance; D000818:Animals; D053148:Caspase 3 / Q000378:metabolism*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D004789:Enzyme Activation / Q000187:drug effects; D006624:Hippocampus / Q000166:cytology*; D008854:Microscopy, Electron / Q000379:methods; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects*; D010446:Peptide Fragments / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000648:ultrastructure; D058225:Plaque, Amyloid / Q000648:ultrastructure; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley
D016229:Amyloid beta-Peptides; C489787:MAP2 protein, rat; D008869:Microtubule-Associated Proteins; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D053148:Caspase 3