title: Isomerization and/or racemization at Asp23 of Abeta42 do not increase its aggregative ability, neurotoxicity, and radical productivity in vitro.
abstract: Aggregation of the 42-mer amyloid beta peptide (Abeta42) plays a pivotal role in the pathogenesis of Alzheimer's disease. Recent investigations suggested the isomerization and/or racemization of Asp at position 1, 7, or 23 to be associated with the pathological role of Abeta42. Our previous study indicated that the turn at positions 22 and 23 of Abeta42 is closely related to its neurotoxicity through the formation of radicals. To clarify the contribution of these modifications at Asp23 to the pathology, three isomerized and/or racemized Abeta42 mutants were prepared. l-isoAsp23- and d-Asp23-Abeta42 showed moderate aggregative ability similar to the wild type. However, d-Asp23-Abeta42 was less neurotoxic than the wild type, while l-isoAsp23-Abeta42 was as toxic as the wild type. In contrast, d-isoAsp23-Abeta42 showed weak aggregative ability without neurotoxicity. These results suggest the isomerization and/or racemization of Asp23 not to be related to the pathogenesis, but to be a consequence of chemical reactions during the long-term deposition of fibrils.
authors: Laboratory of Organic Chemistry in Life Science, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Sakyo-ku, Kyoto 606-8502, Japan.
authors: Kazuma
authors: K
authors: Murakami
authors: Mayumi
authors: M
authors: Uno
authors: Yuichi
authors: Y
authors: Masuda
authors: Takahiko
authors: T
authors: Shimizu
authors: Takuji
authors: T
authors: Shirasawa
authors: Kazuhiro
authors: K
authors: Irie
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites; D002470:Cell Survival / Q000187:drug effects*; D019281:Dimerization; D007536:Isomerism; D009498:Neurotoxins / Q000008:administration & dosage* / Q000737:chemistry*; D016716:PC12 Cells; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D016229:Amyloid beta-Peptides; D009498:Neurotoxins; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42)