Imaging amyloid β peptide oligomeric particles in solution

While all protein misfolding diseases are characterized by fibrous amyloid deposits, the favorable free energy and strongly cooperative nature of the self-assembly have complicated the development of therapeutic strategies aimed at preventing their formation. As structural models for the amyloid fibrils approach atomic resolution, increasing evidence suggests that early folding intermediates, rather than the final structure, are more strongly associated with the loss of neuronal function. For that reason we now demonstrate the use of cryo-etch high-resolution scanning electron microscopy (cryo-HRSEM) for the direct observation of pathway intermediates in amyloid assembly. A congener of the Aβ peptide of Alzheimer’s disease, Aβ(13–21), samples a variety of time-dependent self-assembles in a manner similar to those seen for larger proteins. A morphological description of these intermediates is the first step towards their structural characterization and the definition of their role in both amyloid assembly and neurotoxicity.

Cryo-etch high-resolution scanning electron microscopy (Cryo-HRSEM) was applied for the first time to visualize amyloid β peptide oligomeric particles directly in frozen solution. This approach enables direct visualization of assembly intermediates and may now be used for the evaluation of small molecule probes of structure, stability, stages of self-assembly, and even potential therapeutic intervention for conformational diseases.Figure optionsDownload as PowerPoint slide