title: Inhibition of Aβ42oligomerization in yeast by a PICALM ortholog and certain FDA approved drugs.
abstract: The formation of small Aβ42oligomers 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 Aβ42fused 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 Aβ42oligomerization 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 Aβ42to be less toxic to PC12 cells and to relieve toxicity of another yeast AD model in which Aβ42aggregates targeted to the secretory pathway are toxic. Our results identify drugs that inhibit Aβ42oligomers from forming in yeast. It remains to be determined if these drugs inhibit Aβ42oligomerization in mammals and could be developed as a therapeutic treatment for AD.
authors.affiliation: Present address: Department of Biochemistry and Molecular Biology, University of Nevada, Reno, Reno, NV, USA.
authors.forename: Sei-Kyoung
authors.initials: SK
authors.lastname: Park
authors.affiliation: HTS facility, Research Resources Center, University of Illinois, Chicago, Chicago, IL 60612, USA.
authors.forename: Kiira
authors.initials: K
authors.lastname: Ratia
authors.affiliation: Present address: Department of Biochemistry and Molecular Biology, University of Nevada, Reno, Reno, NV, USA.
authors.forename: Mariam
authors.initials: M
authors.lastname: Ba
authors.affiliation: Present address: Department of Biochemistry and Molecular Biology, University of Nevada, Reno, Reno, NV, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Valencik
authors.affiliation: Present address: Department of Biochemistry and Molecular Biology, University of Nevada, Reno, Reno, NV, USA. ; Department of Biological Sciences, University of Illinois, Chicago, Chicago, IL 60607, USA.
authors.forename: Susan W
authors.initials: SW
authors.lastname: Liebman
keywords: Alzheimer; Aβ42 oligomerization; HTS; PICALM; yeast