Suppression of Mitochondrial Succinate Dehydrogenase, a Primary Target of β‐Amyloid, and Its Derivative Racemized at Ser Residue

β‐Amyloid cores contain considerable amounts of d ‐Ser and d ‐Asp residues in Alzheimer's disease. We investigated the cytotoxic effects of various synthetic β‐amyloids, including d ‐Ser‐substituted derivatives, on primary cultured neurons and nonneuronal HeLa cells. β25–35, its d ‐Ser 26 ‐substituted derivative, and β1–40 in 10–100 n M 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 [ 3 H]Leu and [ 3 H]Tdr. The β‐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 β25–35 and [ d ‐Ser 26 ]β25–35 are dependent on their having β‐structures and not random forms. Although β25–35 was degraded rapidly by proteinase(s) in brain extract or leucine aminopeptidase, [ d ‐Ser 26 ]β25–35 is fairly resistant. These results indicate that one of the primary targets of β‐amyloids is suppression of mitochondrial succinate dehydrogenase, and the vulnerability of the brain to β‐amyloids can be explained by its large dependence on mitochondrial energy production. Moreover, racemization of serine residues of β‐amyloids may be involved in neurodegeneration and formation of senile plaques through escaping from the degradation process by brain proteinases.