Amyloid-beta causes apoptosis of neuronal cells via caspase cascade, which can be prevented by amyloid-beta-derived short peptides

Amyloid beta 1-42 (A beta 42) and A beta 17-42 are major constituents of diffuse plaque in brains with Alzheimer's disease (AD). We demonstrate the potent cytotoxicity of A beta 42 and A beta 17-42, lesser toxicity of A beta 1-40 (A beta 40) and lack of toxicity of A beta 1-16 (A beta 16) in neuronal cells as measured by inhibition of cell proliferative response using thymidine incorporation assay and that this cytotoxicity can be reduced with A beta 16 and eight-residue A beta derivatives such as A beta 1-8 and A beta 9-16. FACS analysis also revealed that A beta 16 could dramatically protect against the apoptosis induced by A beta 17-42 with over 80% viable cells. We determined the caspases involved in the A beta-mediated apoptotic pathway using caspase-specific inhibitors in MTT assays. For all A beta s, the executor was caspase 3, while the initiator was caspase 9 for A beta 42 and caspase 8 for A beta 40 and A beta 17-42. Microscopic observation of lucifer-yellow-labeled neuronal cells demonstrated the occurrence of lysosomal membrane injury of the cells, corresponding to the severe cytotoxic effects of A beta 42. Our findings suggest that the apoptosis of neuronal cells due to A beta 42, A beta 40 and A beta 17-42 is mediated by the different caspase pathways and that this apoptosis can be reduced with the eight-residue A beta-derived fragments A beta 1-8, A beta 9-16 and A beta 16. (c) 2005 Elsevier Inc. All rights reserved.