Inhibition of Aβ42 oligomerization in yeast by a PICALM ortholog and certain FDA approved drugs

Authors:

Sei-Kyoung Park1, Kiira Ratia2, Mariam Ba1, Maria Valencik1 and Susan W. Liebman1,3
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Affiliations:

1 Present address: Department of Biochemistry and Molecular Biology, University of Nevada, Reno, Reno, NV, USA.

2 HTS facility, Research Resources Center, University of Illinois, Chicago, Chicago, IL 60612, USA.

3 Department of Biological Sciences, University of Illinois, Chicago, Chicago, IL 60607, USA.

Keywords: 

Aβ42 oligomerization, yeast, HTS, PICALM, Alzheimer.

Related Article(s)? 

Triana Amen and Daniel Kaganovich (2016). Yeast screening platform identifies FDA-approved drugs that reduce Aβ oligomerization. Microbial Cell 3(3): 97-100. doi: 10.15698/mic2016.03.482, 10.15698/mic2016.03.482

Corresponding Author(s):

Susan W. Liebman, Department of Biochemistry and Molecular Biology, University of Nevada, Reno 1664 N. Virginia Street, Mail stop/330; Reno NV89557, USA sueL@uic.edu

Conflict of interest statement:

The authors declare there is no conflict of interest.

Please cite this article as:

Sei-Kyoung Park, Kiira Ratia, Mariam Ba, Maria Valencik and Susan W. Liebman (2016). Inhibition of Aβ42 oligomerization in yeast by a PICALM ortholog and certain FDA approved drugs. Microbial Cell 3(2): 53-64. doi: 10.15698/mic2016.02.476

© 2016 Park et al. This is an open-access article released under the terms of the Creative Commons Attribution (CC BY) license, which allows the unrestricted use, distribution, and reproduction in any medium, provided the original author and source are acknowledged.

Abstract:

The formation of small Aβ42 oligomers has been implicated as a toxic species in Alzheimer disease (AD). In strong support of this hypothesis we found that overexpression of Yap1802, the yeast ortholog of the human AD risk factor, phosphatidylinositol binding clathrin assembly protein (PICALM), reduced oligomerization of Aβ42 fused to a reporter in yeast. Thus we used the Aβ42-reporter system to identify drugs that could be developed into therapies that prevent or arrest AD. From a screen of 1,200 FDA approved drugs and drug-like small compounds we identified 7 drugs that reduce Aβ42 oligomerization in yeast: 3 antipsychotics (bromperidol, haloperidol and azaperone), 2 anesthetics (pramoxine HCl and dyclonine HCl), tamoxifen citrate, and minocycline HCl. Also, all 7 drugs caused Aβ42 to be less toxic to PC12 cells and to relieve toxicity of another yeast AD model in which Aβ42 aggregates targeted to the secretory pathway are toxic. Our results identify drugs that inhibit Aβ42 oligomers from forming in yeast. It remains to be determined if these drugs inhibit Aβ42 oligomerization in mammals and could be developed as a therapeutic treatment for AD.

doi: 10.15698/mic2016.02.476
Volume 3, pp. 53 to 64, published 20/01/2016.