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Review article2011Peer reviewedOpen access

Protein engineering to stabilize soluble amyloid beta-protein aggregates for structural and functional studies

Härd, Torleif


The molecular biology underlying protein aggregation and neuronal death in Alzheimer's disease is not yet completely understood, but small soluble nonamyloid aggregates of the amyloid beta-protein (A beta) have been shown to play a fundamental neurotoxic role. The composition and biological action of such aggregates, known as oligomers and protofibrils, are therefore areas of intense study. However, research is complicated by the multitude of different interconverting aggregates that A beta can form in vitro and in vivo, and by the inhomogeneity and instability of in vitro preparations. Here we review recent studies in which protein engineering, and in particular disulfide engineering, has been applied to stabilize different A beta aggregates. For example, several techniques now exist to obtain stable and neurotoxic protofibrillar forms of A beta, and engineered A beta dimers, or larger aggregates formed by these, have been shown to specifically induce neuronal damage in a way that mimics Alzheimer's disease pathology. Disulfide engineering has also revealed structural properties of neurotoxic aggregates, for instance that A beta in protofibrils and globular oligomers adopts a beta-hairpin conformation that is similar to, but topologically distinct from, the conformation of A beta in mature amyloid fibrils. Protein engineering is therefore a workable strategy to address many of the outstanding questions relating to the structure, interconversion and biological effects of oligomers and protofibrils of A beta.


Alzheimer's disease; amyloid; amyloid beta-protein; cysteine; disulfide engineering; neurotoxicity; oligomer; protein engineering; protein structure; protofibril

Published in

FEBS Journal
2011, Volume: 278, number: 20, pages: 3884-3892

      SLU Authors

    • Härd, Torleif

      • Department of Molecular Biology, Swedish University of Agricultural Sciences

    UKÄ Subject classification

    Biochemistry and Molecular Biology
    Medical Biotechnology

    Publication identifier


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