The lag between ␤-amyloid (A␤) deposition and neurodegeneration in Alzheimer's disease (AD) suggests that age-dependent factors are involved in the pathogenesis.

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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‐Ser26‐substituted derivative, and β1–40 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 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‐Ser26]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‐Ser26]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.

Oligomeric and fibrillar beta-amyloid (Abeta) may be toxic in Alzheimer disease (AD), especially after post-translation modification cumulative over time. Racemization of Ser and Asp residues of Abeta in senile plaques (SPs) occurs as an age-dependent process in AD. We previously reported that Abeta1-40 racemized at Ser26 is soluble and susceptible to proteolysis yielding toxic [D-Ser26]Abeta25-35/40 fragments in vitro and in vivo. Here, we focus on the localization of racemized Ser26 residues in AD brains within the limbic system, the earliest site of AD histopathology. We developed antisera (20.1 and 22.7). each with epitopes within [D-Ser26]Abeta25-40. Two forms of truncated [D-Ser26]Abeta were detected either in SPs or within neurons in all 11 AD-affected brains, but not in age-matched controls. [D-Ser26]Abeta25/26-35 (detected by 20.1) was localized to plaque cores, extracellular neurofibrillary "ghost" tangles and vascular amyloid deposits. In contrast, [D-Ser26]Abeta25-40 (detected by 22.7) was observed in most neurons containing intracellular neurofibrillary tangles, but not in SPs. These results suggest [D-Ser26]Abeta]1-40, formed during aging, becomes soluble and diffuses from SPs. It is then proteolyzed to [D-Ser26]Abeta25-35/40, which is toxic and may contribute to the neurodegeneration. This hypothesis may explain the long lag between SP formation and neurofibrillary degeneration in AD brains.