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Observation of metastable Abeta amyloid protofibrils by atomic force microscopy
J D Harper1, S S Wong, C M Lieber
1Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
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.
Insights
Researchers identified amyloid beta (Abeta) protofibrils as key intermediates in Alzheimer's disease (AD) amyloid fibril formation. Stabilizing these protofibrils may offer a new therapeutic strategy for AD.
Area of Science:
- Neuroscience
- Biochemistry
- Molecular Biology
Background:
- Alzheimer's disease (AD) is characterized by brain amyloid plaques, primarily composed of beta-amyloid protein (Abeta) variants.
- Abeta amyloid fibrils are implicated in neurodegeneration, making their inhibition a potential therapeutic target.
- The early stages of Abeta fibril formation remain poorly understood.
Purpose of the Study:
- To investigate the initial steps of Abeta fibril formation in vitro.
- To characterize the intermediate species formed during Abeta aggregation.
- To explore potential therapeutic strategies targeting Abeta aggregation.
Main Methods:
- Utilized atomic force microscopy (AFM) to visualize and track amyloid fibril formation.
- Studied two major Abeta variants: Abeta1-40 and Abeta1-42.
Main Results:
- Both Abeta1-40 and Abeta1-42 initially form small, ordered aggregates that are metastable.
- These aggregates disappear as classical amyloid fibrils of two distinct morphologies emerge.
- Abeta1-42 demonstrated significantly faster aggregation kinetics compared to Abeta1-40.
Conclusions:
- Identified and proposed the term 'Abeta amyloid protofibrils' for the metastable intermediate species.
- Abeta protofibrils are likely crucial intermediates in the in vitro assembly of Abeta amyloid fibrils.
- Stabilizing Abeta protofibrils may represent a viable therapeutic approach for Alzheimer's disease.