Racemization: its biological significance on neuropathogenesis of Alzheimer's disease.
Amyloid beta protein (A beta) in neuritic plaques of Alzheimer's disease has been found to be racemized and/or isomerized at their Asp residues. To elucidate the effect of racemization on the aggregation properties of A beta, we synthesized three kinds of A beta peptides in which D-Asp was substituted for L-Asp residues, i.e, normal A beta 1-40, [D-Asp7]A beta 1-40 and [D-Asp23]A beta 1-40. The aggregation and fibril formation of each peptide was examined by means of spectrofluorometry and electron microscopy. Of the three peptides, normal A beta showed the gradual increase of aggregation while [D-Asp7]A beta 1-40 and [D-Asp23] A beta 1-40 showed more enhanced aggregation at the final stage when the fibril formations were detected in all peptides solutions by electron microscopy. A comparative immunohistochemical study by anti-racemized A beta antibody and anti-A beta 1-42/43 antibody further showed the in vivo incorporation of D-Asp in senile plaques of Alzheimer's disease brains, which may be involved in plaque formation at the later stage than the deposition of the longer form of A beta (A beta 1-42/43). Taken together with the recent accumulated evidence on the aggregation mechanisms of A beta, the data presented here suggest that racemization may occur after the amyloid fibril formation but enhance the aggregation process by shifting the equilibrium of A beta from the soluble form to the insoluble form in Alzheimer's disease.
Mori
H
H
Department of Molecular Biology, Tokyo Institute of Psychiatry.
Ishii
K
K
Tomiyama
T
T
Furiya
Y
Y
Sahara
N
N
Asano
S
S
Endo
N
N
Shirasawa
T
T
Takio
K
K
D000544:Alzheimer Disease / Q000209:etiology* / Q000378:metabolism; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism; D001224:Aspartic Acid / Q000737:chemistry; D001704:Biopolymers / Q000737:chemistry; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007536:Isomerism; D008854:Microscopy, Electron; D008969:Molecular Sequence Data; D009410:Nerve Degeneration; D009419:Nerve Tissue Proteins / Q000737:chemistry*; D010446:Peptide Fragments / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism; D011485:Protein Binding; D012995:Solubility; D013050:Spectrometry, Fluorescence; D013237:Stereoisomerism
D016229:Amyloid beta-Peptides; D001704:Biopolymers; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); D001224:Aspartic Acid