Observation of metastable A beta amyloid protofibrils by atomic force microscopy

被引:625
作者
Harper, JD
Wong, SS
Lieber, CM
Lansbury, PT
机构
[1] HARVARD UNIV,DEPT CHEM & BIOL CHEM,CAMBRIDGE,MA 02138
[2] MIT,DEPT CHEM,CAMBRIDGE,MA 02139
[3] BRIGHAM & WOMENS HOSP,CTR NEUROL DIS,BOSTON,MA 02115
[4] HARVARD UNIV,SCH MED,BOSTON,MA 02115
来源
CHEMISTRY & BIOLOGY | 1997年 / 4卷 / 02期
关键词
amyloid; atomic force microscopy; protofibril;
D O I
10.1016/S1074-5521(97)90255-6
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Background: Brain amyloid plaque, a diagnostic feature of Alzheimer's disease (AD), contains an insoluble fibrillar core that is composed primarily of variants of the beta-amyloid protein (A beta). As A beta amyloid fibrils may initiate neurodegeneration, the inhibition of fibril formation is a possible therapeutic strategy, Very little is known about the early steps of the process, however. Results: Atomic force microscopy was used to follow amyloid fibril formation in vitro by the A beta variants A beta 1-40 and A beta 1-42. Both variants first form small ordered aggregates that grow slowly and then rapidly disappear, while prototypical amyloid fibrils of two discrete morphologies appear. A beta 1-42 aggregates much more rapidly than A beta 1-40, which is consistent with its connection to early-onset AD. We propose that the metastable intermediate species be called A beta amyloid protofibrils, Conclusions: A beta protofibrils are likely to be intermediates in the in vitro assembly of A beta amyloid fibrils, but their in vivo role has yet to be determined. Numerous reports of a nonfibrillar form of A beta aggregate in the brains of individuals who are predisposed to AD suggest the existence of a precursor form, possibly the protofibril, Thus, stabilization of A beta protofibrils may be a useful therapeutic strategy.
引用
收藏
页码:119 / 125
页数:7
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