[Amyloidogenic peptides such as beta-amyloid, amylin and calcitonin strongly enhance the susceptibility of rat hippocampal neurons to excitatory amino acids in vivo].
We have previously shown that in vivo injection of beta-amyloid (beta 1-40, beta 25-35) with non-toxic amounts of ibotenic acid, an excitatory amino acid, causes synergistic and drastic neuronal degeneration in rat hippocampus. It was, however, yet not clear whether the neuronal degeneration in vivo was associated with their primary amino acid sequences, their secondary beta-structure or their activities to suppress MTT reduction activity in vitro. In addition to beta-amyloid, other amyloidogenic peptides such as human amylin or calcitonin are known to deposit extracellularly in systemic and peripheral amyloidosis. In this study, we measured the activity of amyloidogenic peptides (beta 1-40, human amylin and calcitonin) to suppress cellular MTT reduction activity in vitro and their synergistic neurodegeneration with ibotenic acid in vivo. All amyloidogenic peptides, but not non-amyloidogenic peptides (beta 40-1, BSA), suppressed the MTT reduction activity in HeLa cells and in the primary cultured neurons in vitro, and also produced the synergistic neuronal cell loss in rat hippocampal region by enhancing the toxicity of ibotenic acid in vivo. The deposits of amyloidogenic peptides at the injection sites were thioflavin S fluorescence positive, suggesting the fibrillary beta-structures. These results indicate that the neurodegeneration in vivo by amyloidogenic peptides is strongly associated with their fibrillary beta-structure and their activity to suppress MTT reduction activity in vitro.
Morimoto
K
K
Neuroscience Research Laboratories, Sankyo Co., Ltd., Tokyo, Japan.
Nagata
S
S
Kubo
T
T
Oda
T
T
Kaneko
I
I
D000682:Amyloid / Q000494:pharmacology*; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D002116:Calcitonin / Q000494:pharmacology*; D002478:Cells, Cultured; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018846:Excitatory Amino Acids / Q000494:pharmacology*; D006367:HeLa Cells; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects*; D006801:Humans; D007051:Ibotenic Acid / Q000494:pharmacology; D058228:Islet Amyloid Polypeptide; D009410:Nerve Degeneration; D009474:Neurons / Q000187:drug effects*; D010084:Oxidation-Reduction; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D013778:Tetrazolium Salts / Q000378:metabolism
D000682:Amyloid; D016229:Amyloid beta-Peptides; D018690:Excitatory Amino Acid Agonists; D018846:Excitatory Amino Acids; D058228:Islet Amyloid Polypeptide; D013778:Tetrazolium Salts; D007051:Ibotenic Acid; D002116:Calcitonin