Reaffirming ‘Amyloid Surprises’ | Chemical & Engineering News
Volume 90 Issue 20 | pp. 2-4 | Letters
Issue Date: May 14, 2012

Reaffirming ‘Amyloid Surprises’

Department: Letters

The article “Amyloid Surprises” accurately summarizes the interesting findings by research teams led by David Eisenberg of the University of California, Los Angeles, and Charles G. Glabe of UC Irvine (C&EN, March 19, page 38). They report that an 11-residue polypeptide, with similarities to amphipathic β-sheets in several amyloids, including the Alzheimer’s disease amyloid-β (Aβ), forms a barrel-like hexamer of antiparallel β-sheets in solution.

The work is reminiscent of a C&EN article that summarized the discovery by Nelson Arispe, Eduardo Rojas, and me at the National Institutes of Health that the Alz­heimer’s disease Aβ forms neurotoxic calcium channels in lipid bilayers and neuronal membranes (Jan. 25, 1993, page 5). At the time, this finding was sufficiently important to also warrant a half-page above-the-fold article in the Washington Post (Boyce Rensberger, Jan. 25, 1993, page A3). The Post even featured a sketch of the “pore” through which calcium entered the cell.

A few months later, we showed that the most energetically favorable model for the Aβ channel was indeed a hexamer of Aβ subunits. The model featured antiparallel β-sheets, forming a cylindrical, barrel-like pore through which calcium ions crossed the membrane [Biophys. J., DOI: 10.1016/S0006-3495(94)80717-9]. The proposed structure was based on a combination of our electrophysiological work and molecular dynamic simulation experiments performed in collaboration with H. Robert Guy and colleagues at NIH. Shortly thereafter, the Biophysical Society devoted an entire symposium to this discovery at its annual meeting in San Francisco.

However, the study described in the recent C&EN article uses somewhat different methods than the ones used by our original group and many, many others, working from 1993 to the present. It seems that the cylindrin structure models a region of Aβ that is not exactly in the pore domain predicted by our 1994 model, although it is in the neighborhood of the true pore domain in Aβ. While it appears, therefore, to reflect the intrinsic hexameric structure of the true pore, as reported, cylindrin itself neither supports conductance of calcium nor efficiently kills cells.

Finally, as suggested in the current C&EN article, the implications of an active pore might be very important for discovery of drugs effective against amyloid-based degenerative diseases. For example, collaborating with medicinal chemist Kenneth Jacobson at NIH, we designed and synthesized compounds that were able to dock precisely with the predicted antiparallel Aβ “pore.” These compounds also potently blocked calcium conductance and protected neurons from Aβ-mediated neurotoxicity (Proc. Natl. Acad. Sci.USA, DOI: 10.1073/pnas.0813355106).

In conclusion, we are glad to see this article and view it as an elegant complement to the previous work by our group and others, in that it is consistent with what is known to be the Aβ pore structure and further contributes to a drug discovery candidate mechanism for Aβ neurotoxicity.

By Harvey B. Pollard
Bethesda, Md

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