Suppression of mitochondrial succinate dehydrogenase, a primary target of beta-amyloid, and its derivative racemized at Ser residue.
beta-Amyloid cores contain considerable amounts of D-Ser and D-Asp residues in Alzheimer's disease. We investigated the cytotoxic effects of various synthetic beta-amyloids, including D-Ser-substituted derivatives, on primary cultured neurons and nonneuronal HeLa cells. beta 25-35, its D-Ser26-substituted derivative, and beta 1-40 in 10-100 nM specifically suppressed mitochondrial succinate dehydrogenase activity [MTT [3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide] reduction] in HeLa cells, which are dependent on ATP production mainly from glycolysis, but did not exert detectable cytotoxicity, assessed by dye exclusion test, NADH levels, and uptake of [3H]Leu and [3H]Tdr. The beta-amyloids, on the other hand, did exert neurodegenerative effects on rat hippocampal cultured neurons in which ATP is mostly synthesized by the mitochondrion. The activities of beta 25-35 and [D-Ser26] beta 25-35 are dependent on their having beta-structures and not random forms. Although beta 25-35 was degraded rapidly by proteinase(s) in brain extract or leucine aminopeptidase, [D-Ser26] beta 25-35 is fairly resistant. These results indicate that one of the primary targets of beta-amyloids is suppression of mitochondrial succinate dehydrogenase, and the vulnerability of the brain of beta-amyloids can be explained by its large dependence on mitochondrial energy production. Moreover, racemization of serine residues of beta-amyloids may be involved in neurodegeneration and formation of senile plaques through escaping from the degradation process by brain proteinases.
Kaneko
I
I
Neuroscience Research Laboratories, Sankyo Co., Ltd., Tokyo, Japan.
Yamada
N
N
Sakuraba
Y
Y
Kamenosono
M
M
Tutumi
S
S
D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001923:Brain Chemistry; D002470:Cell Survival / Q000187:drug effects; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects; D008928:Mitochondria / Q000201:enzymology*; D009474:Neurons / Q000187:drug effects; D010084:Oxidation-Reduction / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D013385:Succinate Dehydrogenase / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D013778:Tetrazolium Salts / Q000378:metabolism; D013844:Thiazoles / Q000378:metabolism; D014020:Tissue Extracts / Q000494:pharmacology
D016229:Amyloid beta-Peptides; D013778:Tetrazolium Salts; D013844:Thiazoles; D014020:Tissue Extracts; D013385:Succinate Dehydrogenase; C022616:thiazolyl blue