[PDF][PDF] Observation of metastable Aβ 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 β-amyloid
protein (Aβ). As Aβ 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 Aβ variants Aβ1-40 and Aβ1-42. Both variants first form small …
contains an insoluble fibrillar core that is composed primarily of variants of the β-amyloid
protein (Aβ). As Aβ 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 Aβ variants Aβ1-40 and Aβ1-42. Both variants first form small …
Abstract
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 β-amyloid protein (Aβ). As Aβ 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 Aβ variants Aβ1-40 and Aβ1-42. Both variants first form small ordered aggregates that grow slowly and then rapidly disappear, while prototypical amyloid fibrils of two discrete morphologies appear. Aβ1-42 aggregates much more rapidly than Aβ1-40, which is consistent with its connection to early-onset AD. We propose that the metastable intermediate species be called Aβ amyloid protofibrils.
Conclusions: Aβ protofibrils are likely to be intermediates in the in vitro assembly of Aβ amyloid fibrils, but their in vivo role has yet to be determined. Numerous reports of a nonfibrillar form of Aβ aggregate in the brains of individuals who are predisposed to AD suggest the existence of a precursor form, possibly the protofibril. Thus, stabilization of Aβ protofibrils may be a useful therapeutic strategy.
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