期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2003
卷号：100
期号：11
页码：6370-6375
DOI：10.1073/pnas.1237107100
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：{beta}-Amyloid (A{beta}) acquires toxicity by self-aggregation. To identify and characterize the toxic form(s) of A{beta} aggregates, we examined in vitro aggregation conditions by using large quantities of homogenous, chemically synthesized A{beta}1-40 peptide. We found that slow rotation of A{beta}1-40 solution reproducibly gave self-aggregated A{beta}1-40 containing a stable and highly toxic moiety. Examination of the aggregates purified by glycerol-gradient centrifugation by atomic force microscopy and transmission electron microscopy revealed that the toxic moiety is a perfect sphere, which we call amylospheroid (ASPD). Other A{beta}1-40 aggregates, including fibrils, were nontoxic. Correlation studies between toxicity and sphere size indicate that 10- to 15-nm ASPD was highly toxic, whereas ASPD <10 nm was nontoxic. A positive correlation between the toxicity and ASPD >10 nm also appeared to exist when A{beta}1-42 formed ASPD by slow rotation. However, A{beta}1-42-ASPD formed more rapidly, killed neurons at lower concentrations, and showed {approx}100-fold-higher toxicity than A{beta}1-40-ASPD. The toxic ASPD was associated with SDS-resistant oligomeric bands in immunoblotting, which were absent in nontoxic ASPD. Because the formation of ASPD was not disturbed by pentapeptides that break {beta}-sheet interactions, A{beta} may form ASPD through a pathway that is at least partly distinct from that of fibril formation. Inhibition experiments with lithium suggest the involvement of tau protein kinase I/glycogen synthase kinase-3{beta} in the early stages of ASPD-induced neurodegeneration. Here we describe the identification and characterization of ASPD and discuss its possible role in the neurodegeneration in Alzheimer's disease.
