Inhibition of A beta(42) oligomerization in yeast by a PICALM ortholog and certain FDA approved drugs
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Authors
Park, Sei-Kyoung
Ratia, Kiira
Ba, Mariam A.
Valencik, Maria L.
Liebman, Susan W.
Issue Date
2016
Type
Article
Language
Keywords
A?42 oligomerization , yeast , HTS , PICALM , Alzheimer
Alternative Title
Abstract
The formation of small A beta 42 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 A beta 42 fused to a reporter in yeast. Thus we used the A beta 42-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 A beta 42 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 A beta 42 to be less toxic to PC12 cells and to relieve toxicity of another yeast AD model in which A beta 42 aggregates targeted to the secretory pathway are toxic. Our results identify drugs that inhibit A beta 42 oligomers from forming in yeast. It remains to be determined if these drugs inhibit A beta 42 oligomerization in mammals and could be developed as a therapeutic treatment for AD.
Description
Citation
Park, S.-K., Ratia, K., Ba, M., Valencik, M., & Liebman, S. (2016). Inhibition of A?42 oligomerization in yeast by a PICALM ortholog and certain FDA approved drugs. Microbial Cell, 3(2), 53�"64. doi:10.15698/mic2016.02.476
Publisher
License
Creative Commons Attribution 4.0 International
Journal
Volume
Issue
PubMed ID
ISSN
2311-2638