Observation of metastable A beta amyloid protofibrils by atomic force microscopy

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.