{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T23:08:49Z","timestamp":1791068929836,"version":"4.1.0"},"reference-count":26,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2002,10,18]],"date-time":"2002-10-18T00:00:00Z","timestamp":1034899200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J of Neuroscience Research"],"published-print":{"date-parts":[[2002,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The lag between \u03b2\u2010amyloid (A\u03b2) deposition and neurodegeneration in Alzheimer's disease (AD) suggests that age\u2010dependent factors are involved in the pathogenesis. Racemization of Ser and Asp in A\u03b2 is a typical age\u2010dependent modification in AD. We have shown recently that A\u03b21\u201340 racemized at Ser<jats:sup>26<\/jats:sup> ([<jats:sc>D<\/jats:sc>\u2010Ser<jats:sup><jats:sc>26<\/jats:sc><\/jats:sup>]A\u03b21\u201340) is soluble and non\u2010toxic to neuronal cells, but is easily converted by brain proteases to truncated toxic fragments, [<jats:sc>D<\/jats:sc>\u2010Ser<jats:sup><jats:sc>26<\/jats:sc><\/jats:sup>]A\u03b225\u201335\/40. Furthermore, [<jats:sc>D<\/jats:sc>\u2010Ser<jats:sup><jats:sc>26<\/jats:sc><\/jats:sup>]A\u03b21\u201340 in vivo, produced a drastic and synergistic neuronal loss by enhancing the excitotoxicity when co\u2010injected into rat hippocampus with ibotenic acid, an excitatory amino acid, suggesting an in vivo conversion of non\u2010toxic [<jats:sc>D<\/jats:sc>\u2010Ser<jats:sup>26<\/jats:sup>]A\u03b21\u201340 to toxic fragments including [<jats:sc>D<\/jats:sc>\u2010Ser<jats:sup>26<\/jats:sup>]A\u03b225\u201335\/40. In this study, we further investigated the mechanism behind the in vivo neuronal loss by [<jats:sc>D<\/jats:sc>\u2010Ser<jats:sup>26<\/jats:sup>]A\u03b21\u201340 and ibotenic acid in rats, and also searched for the presence of [<jats:sc>D<\/jats:sc>\u2010Ser<jats:sup>26<\/jats:sup>]A\u03b225\u201335\/40 antigens in AD brains. Quantitative analyses of the damaged area indicate clearly that non\u2010toxic [<jats:sc>D<\/jats:sc>\u2010Ser<jats:sup>26<\/jats:sup>]A\u03b21\u201340 caused as much neurodegeneration as toxic [<jats:sc>D<\/jats:sc>\u2010Ser<jats:sup>26<\/jats:sup>]A\u03b225\u201335\/40. MK\u2010801, an NMDA receptor antagonist, completely inhibited the neurodegeneration. The immunohistochemical analyses using anti\u2010[<jats:sc>D<\/jats:sc>\u2010Ser<jats:sup>26<\/jats:sup>]A\u03b225\u201335\/40\u2010specific antibodies demonstrated the presence of [<jats:sc>D<\/jats:sc>\u2010Ser<jats:sup>26<\/jats:sup>]A\u03b225\u201335\/40 antigens in senile plaques and in degenerating hippocampal CA1 neurons in AD brains, but not in age\u2010matched control brains. These results strengthen our hypothesis that soluble [<jats:sc>D<\/jats:sc>\u2010Ser<jats:sup>26<\/jats:sup>]A\u03b21\u201340, possibly produced during aging, is released from plaques and converted by proteolysis to toxic [<jats:sc>D<\/jats:sc>\u2010Ser<jats:sup>26<\/jats:sup>]A\u03b225\u201335\/40, which damage hippocampal CA1 neurons by enhancing excitotoxicity in AD. This may account for the lag between A\u03b2 deposition and neurodegeneration in AD. \u00a9 2002 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/jnr.10391","type":"journal-article","created":{"date-parts":[[2002,10,22]],"date-time":"2002-10-22T14:37:14Z","timestamp":1035297434000},"page":"474-483","source":"Crossref","is-referenced-by-count":236,"title":["In vivo conversion of racemized \u03b2\u2010amyloid ([<scp>D<\/scp>\u2010Ser<sup>26<\/sup>]A\u03b21\u201340) to truncated and toxic fragments ([<scp>D<\/scp>\u2010Ser<sup>26<\/sup>]A\u03b225\u201335\/40) and fragment presence in the brains of Alzheimer's 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