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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
Author(s) -
Kubo Takekazu,
Nishimura Satoko,
Kumagae Yoshihiro,
Kaneko Isao
Publication year - 2002
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/jnr.10391
Subject(s) - ibotenic acid , neurodegeneration , in vivo , chemistry , amyloid beta , excitotoxicity , amyloid (mycology) , biochemistry , beta (programming language) , proteases , nmda receptor , microbiology and biotechnology , receptor , biology , endocrinology , medicine , enzyme , peptide , inorganic chemistry , computer science , programming language , central nervous system , disease
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.