Observation of metastable Aβ amyloid protofibrils by atomic force microscopy

作者：James D. Harper, Stanislaus S. Wong, Charles M. Lieber, Peter T. Lansbury · 发表于：Chemistry & Biology · 年份：1997 · DOI：10.1016/s1074-5521(97)90255-6 · 被引用次数：698 · 研究领域：Alzheimer's disease research and treatments、Neurogenesis and neuroplasticity mechanisms、Supramolecular Self-Assembly in Materials

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 (Abeta). As Abeta 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 Abeta variants Abeta1-40 and Abeta1-42. Both variants first form small ordered aggregates that grow slowly and then rapidly disappear, while prototypical amyloid fibrils of two discrete morphologies appear. Abeta1-42 aggregates much more rapidly than Abeta1-40, which is consistent with its connection to early-onset AD. We propose that the metastable intermediate species be called Abeta amyloid protofibrils. CONCLUSIONS: Abeta protofibrils are likely to be intermediates in the in vitro assembly of Abeta amyloid fibrils, but their in vivo role has yet to be determined. Numerous reports of a nonfibrillar form of Abeta aggregate in the brains of individuals who are predisposed to AD suggest the existence of a precursor form, possibly the protofibril. Thus, stabilization of Abeta protofibrils may be a useful therapeutic strategy.