Drastic neuronal loss in vivo by beta-amyloid racemized at Ser(26) residue: conversion of non-toxic [D-Ser(26)]beta-amyloid 1-40 to toxic and proteinase-resistant fragments.
It is unclear how and when insoluble beta-amyloid in senile plaques exerts degenerative effects on distant hippocampal neurons in Alzheimer's disease. Racemization of Ser and Asp residues of insoluble beta-amyloid is a typical age-dependent process. In this study, we investigated the fibril formation activity and cytotoxic activity of beta-amyloid 1-40 racemized at the Asp or Ser residue. In contrast to beta-amyloid 1-40 and its derivative substituted with the D-Asp(1, 7 or 23) or D-Ser(8) residue, [D-Ser(26)]beta-amyloid 1-40 was non-toxic to PC12 cells, and did not exhibit significant fibril formation activity making it soluble. However, [D-Ser(26)]beta-amyloid 1-40, but not beta-amyloid 1-40, was converted in vitro to a potent neurotoxic and truncated peptide, [D-Ser(26)]beta-amyloid 25-35 or [D-Ser(26)]beta-amyloid 25-40, by chymotrypsin-like enzymes and aminopeptidase M. Soluble [D-Ser(26)]beta-amyloid 1-40 was injected into rat hippocampus with a non-toxic dose of ibotenic acid, an excitatory amino acid. Nissl staining and microtubule-associated protein-2 immunostaining revealed that [D-Ser(26)]beta-amyloid 1-40, as well as [D-Ser(26)]beta-amyloid 25-35, produced a drastic degeneration of the CA1 neurons with ibotenic acid although [D-Ser(26)]beta-amyloid 1-40 alone or ibotenic acid alone did not exert neuronal damage. This suggests the in vivo conversion of non-toxic [D-Ser(26)]beta-amyloid 1-40 to the toxic and truncated peptides which enhance the susceptibility of neurons to the excitatory amino acid.These results and the presence of [D-Ser(26)]beta-amyloid 25-35-like antigens in Alzheimer's disease brains suggest that soluble [D-Ser(26)]beta-amyloid 1-40, possibly formed during the aging process, is released from senile plaques, and converted by brain proteinases to truncated [D-Ser(26)]beta-amyloid 25-35(40)-like peptides, which degenerate hippocampal neurons by enhancing the susceptibility to excitatory amino acids in Alzheimer's disease brains. These findings may provide the basis for a new therapeutic approach to prevent the neurodegeneration in Alzheimer's disease.
Kaneko
I
I
Neuroscience and Immunology Research Laboratories, Sankyo Co., Ltd., 1-2-58, Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan. kaneko@shina.sankyo.co.jp
Morimoto
K
K
Kubo
T
T
D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D000591:Amino Acid Isomerases / Q000378:metabolism / Q000494:pharmacology; D000595:Amino Acid Sequence / Q000502:physiology; D000626:Aminopeptidases / Q000493:pharmacokinetics; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics / Q000633:toxicity*; D000818:Animals; D001224:Aspartic Acid / Q000737:chemistry / Q000378:metabolism; D002918:Chymotrypsin / Q000493:pharmacokinetics; D004396:Coloring Agents / Q000493:pharmacokinetics; D010450:Endopeptidases / Q000378:metabolism / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007051:Ibotenic Acid / Q000633:toxicity; D008297:Male; D009410:Nerve Degeneration / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D016874:Neurofibrillary Tangles / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D016716:PC12 Cells / Q000187:drug effects / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics / Q000633:toxicity*; D058225:Plaque, Amyloid / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012694:Serine / Q000737:chemistry / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D004396:Coloring Agents; D018690:Excitatory Amino Acid Agonists; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C074636:amyloid beta-protein (25-35); D007051:Ibotenic Acid; D001224:Aspartic Acid; D012694:Serine; D010450:Endopeptidases; D000626:Aminopeptidases; D002918:Chymotrypsin; D000591:Amino Acid Isomerases