In vivo conversion of racemized β‐amyloid ([D‐Ser26]Aβ1–40) to truncated and toxic fragments ([D‐Ser26]Aβ25–35/40) and fragment presence in the brains of Alzheimer's patients

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Abstract
The lag between β-amyloid (Aβ) deposition and neurodegeneration in Alzheimer's disease (AD) suggests that age-dependent factors are involved in the pathogenesis. Racemization of Ser and Asp in Aβ is a typical age-dependent modification in AD. We have shown recently that Aβ1–40 racemized at Ser26 ([D-Ser26]Aβ1–40) is soluble and non-toxic to neuronal cells, but is easily converted by brain proteases to truncated toxic fragments, [D-Ser26]Aβ25–35/40. Furthermore, [D-Ser26]Aβ1–40 in vivo, produced a drastic and synergistic neuronal loss by enhancing the excitotoxicity when co-injected into rat hippocampus with ibotenic acid, an excitatory amino acid, suggesting an in vivo conversion of non-toxic [D-Ser26]Aβ1–40 to toxic fragments including [D-Ser26]Aβ25–35/40. In this study, we further investigated the mechanism behind the in vivo neuronal loss by [D-Ser26]Aβ1–40 and ibotenic acid in rats, and also searched for the presence of [D-Ser26]Aβ25–35/40 antigens in AD brains. Quantitative analyses of the damaged area indicate clearly that non-toxic [D-Ser26]Aβ1–40 caused as much neurodegeneration as toxic [D-Ser26]Aβ25–35/40. MK-801, an NMDA receptor antagonist, completely inhibited the neurodegeneration. The immunohistochemical analyses using anti-[D-Ser26]Aβ25–35/40-specific antibodies demonstrated the presence of [D-Ser26]Aβ25–35/40 antigens in senile plaques and in degenerating hippocampal CA1 neurons in AD brains, but not in age-matched control brains. These results strengthen our hypothesis that soluble [D-Ser26]Aβ1–40, possibly produced during aging, is released from plaques and converted by proteolysis to toxic [D-Ser26]Aβ25–35/40, which damage hippocampal CA1 neurons by enhancing excitotoxicity in AD. This may account for the lag between Aβ deposition and neurodegeneration in AD.