Amyloid-beta causes apoptosis of neuronal cells via caspase cascade, which can be prevented by amyloid-beta-derived short peptides.
Amyloid beta 1-42 (Abeta42) and Abeta17-42 are major constituents of diffuse plaque in brains with Alzheimer's disease (AD). We demonstrate the potent cytotoxicity of Abeta42 and Abeta17-42, lesser toxicity of Abeta1-40 (Abeta40) and lack of toxicity of Abeta1-16 (Abeta16) in neuronal cells as measured by inhibition of cell proliferative response using thymidine incorporation assay and that this cytotoxicity can be reduced with Abeta16 and eight-residue Abeta derivatives such as Abeta1-8 and Abeta9-16. FACS analysis also revealed that Abeta16 could dramatically protect against the apoptosis induced by Abeta17-42 with over 80% viable cells. We determined the caspases involved in the Abeta-mediated apoptotic pathway using caspase-specific inhibitors in MTT assays. For all Abetas, the executor was caspase 3, while the initiator was caspase 9 for Abeta42 and caspase 8 for Abeta40 and Abeta17-42. 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 Abeta42. Our findings suggest that the apoptosis of neuronal cells due to Abeta42, Abeta40 and Abeta17-42 is mediated by the different caspase pathways and that this apoptosis can be reduced with the eight-residue Abeta-derived fragments Abeta1-8, Abeta9-16 and Abeta16.
Awasthi
Aradhana
A
Fifth Department of Internal Medicine, School of Medicine, Fukuoka University, Fukuoka 814-0180, Japan.
Matsunaga
Yoichi
Y
Yamada
Tatsuo
T
D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000633:toxicity*; D000704:Analysis of Variance; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry / Q000379:methods; D006801:Humans; D008247:Lysosomes / Q000187:drug effects; D009447:Neuroblastoma; D009474:Neurons / Q000187:drug effects*; D010446:Peptide Fragments / Q000145:classification / Q000494:pharmacology*; D013778:Tetrazolium Salts; D013844:Thiazoles
D016229:Amyloid beta-Peptides; D004791:Enzyme Inhibitors; D010446:Peptide Fragments; D013778:Tetrazolium Salts; D013844:Thiazoles; D020169:Caspases; C022616:thiazolyl blue