In vivo conversion of racemized β‐amyloid ([ D ‐Ser 26 ]Aβ1–40) to truncated and toxic fragments ([ D ‐Ser 26 ]Aβ25–35/40) and fragment presence in the brains of Alzheimer's patients

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 Ser 26 ([ D ‐Ser 26 ]Aβ1–40) is soluble and non‐toxic to neuronal cells, but is easily converted by brain proteases to truncated toxic fragments, [ D ‐Ser 26 ]Aβ25–35/40. Furthermore, [ D ‐Ser 26 ]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 ‐Ser 26 ]Aβ1–40 to toxic fragments including [ D ‐Ser 26 ]Aβ25–35/40. In this study, we further investigated the mechanism behind the in vivo neuronal loss by [ D ‐Ser 26 ]Aβ1–40 and ibotenic acid in rats, and also searched for the presence of [ D ‐Ser 26 ]Aβ25–35/40 antigens in AD brains. Quantitative analyses of the damaged area indicate clearly that non‐toxic [ D ‐Ser 26 ]Aβ1–40 caused as much neurodegeneration as toxic [ D ‐Ser 26 ]Aβ25–35/40. MK‐801, an NMDA receptor antagonist, completely inhibited the neurodegeneration. The immunohistochemical analyses using anti‐[ D ‐Ser 26 ]Aβ25–35/40‐specific antibodies demonstrated the presence of [ D ‐Ser 26 ]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 ‐Ser 26 ]Aβ1–40, possibly produced during aging, is released from plaques and converted by proteolysis to toxic [ D ‐Ser 26 ]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. © 2002 Wiley‐Liss, Inc.