Drastic neuronal loss in vivo by β-amyloid racemized at Ser26 residue:: conversion of non-toxic [D-Ser26]β-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 CAI 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. (C) 2001 IBRO. Published by Elsevier Science Ltd. All rights reserved.