title: In vivo conversion of racemized beta-amyloid ([D-Ser 26]A beta 1-40) to truncated and toxic fragments ([D-Ser 26]A beta 25-35/40) and fragment presence in the brains of Alzheimer's patients.
abstract: The lag between beta-amyloid (A beta) deposition and neurodegeneration in Alzheimer's disease (AD) suggests that age-dependent factors are involved in the pathogenesis. Racemization of Ser and Asp in A beta is a typical age-dependent modification in AD. We have shown recently that A beta1-40 racemized at Ser(26) ([D-Ser(26)]A beta 1-40) is soluble and non-toxic to neuronal cells, but is easily converted by brain proteases to truncated toxic fragments, [D-Ser(26)]A beta 25-35/40. Furthermore, [D-Ser(26)]A beta1-40 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)]A beta1-40 to toxic fragments including [D-Ser(26)]A beta 25-35/40. In this study, we further investigated the mechanism behind the in vivo neuronal loss by [D-Ser(26)]A beta1-40 and ibotenic acid in rats, and also searched for the presence of [D-Ser(26)]A beta 25-35/40 antigens in AD brains. Quantitative analyses of the damaged area indicate clearly that non-toxic [D-Ser(26)]A beta 1-40 caused as much neurodegeneration as toxic [D-Ser(26)]A beta 25-35/40. MK-801, an NMDA receptor antagonist, completely inhibited the neurodegeneration. The immunohistochemical analyses using anti-[D-Ser(26)]A beta 25-35/40-specific antibodies demonstrated the presence of [D-Ser(26)]A beta 25-35/40 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)]A beta1-40, possibly produced during aging, is released from plaques and converted by proteolysis to toxic [D-Ser(26)]A beta 25-35/40, which damage hippocampal CA1 neurons by enhancing excitotoxicity in AD. This may account for the lag between A beta deposition and neurodegeneration in AD.
authors.affiliation: Biological Research Laboratories and Sankyo Research Institute, Sankyo, Shinagawa-ku, Tokyo, Japan.
authors.forename: Takekazu
authors.initials: T
authors.lastname: Kubo
authors.forename: Satoko
authors.initials: S
authors.lastname: Nishimura
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kumagae
authors.forename: Isao
authors.initials: I
authors.lastname: Kaneko
mesh_terms: D000368:Aged; D000375:Aging / Q000378:metabolism*; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D000591:Amino Acid Isomerases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000633:toxicity; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D001921:Brain / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D007051:Ibotenic Acid; D008297:Male; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D009498:Neurotoxins / Q000494:pharmacology; D016716:PC12 Cells; D010446:Peptide Fragments / Q000378:metabolism / Q000633:toxicity; D058225:Plaque, Amyloid / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012694:Serine / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D009498:Neurotoxins; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C074636:amyloid beta-protein (25-35); D007051:Ibotenic Acid; D012694:Serine; D000591:Amino Acid Isomerases