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Inhibition of Aβ42 oligomerization in yeast by a PICALM ortholog and certain FDA approved drugs
Sei-Kyoung Park1, Kiira Ratia2, Mariam Ba1
1Present address: Department of Biochemistry and Molecular Biology, University of Nevada, Reno, Reno, NV, USA.
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.
Insights
Researchers identified 7 drugs that reduce toxic amyloid-beta (Aβ42) oligomer formation in yeast, a key factor in Alzheimer disease (AD). These compounds show potential for developing new AD therapies.
Area of Science:
- Neuroscience
- Biochemistry
- Pharmacology
Background:
- Small amyloid-beta (Aβ42) oligomers are toxic species implicated in Alzheimer disease (AD).
- Phosphatidylinositol binding clathrin assembly protein (PICALM) is a human AD risk factor, and its yeast ortholog, Yap1802, influences Aβ42 oligomerization.
- A yeast model using Aβ42 fused to a reporter was employed to study oligomerization.
Purpose of the Study:
- To identify drugs that inhibit Aβ42 oligomerization using a yeast-based screening system.
- To find potential therapeutic agents for preventing or arresting Alzheimer disease.
Main Methods:
- A yeast reporter system was used to monitor Aβ42 oligomerization.
- A screen of 1,200 FDA-approved drugs and drug-like compounds was conducted.
- The toxicity of identified compounds on PC12 cells and another yeast AD model was assessed.
Main Results:
- Seven drugs were identified that reduce Aβ42 oligomerization in yeast: bromperidol, haloperidol, azaperone, pramoxine HCl, dyclonine HCl, tamoxifen citrate, and minocycline HCl.
- All 7 identified drugs reduced Aβ42 toxicity in PC12 cells.
- These drugs also alleviated toxicity in a yeast model involving secretory pathway-targeted Aβ42 aggregates.
Conclusions:
- The study identified specific drugs that inhibit Aβ42 oligomer formation in a yeast model.
- These findings suggest potential therapeutic avenues for Alzheimer disease by targeting Aβ42 oligomerization.
- Further investigation is needed to confirm efficacy in mammalian systems for AD treatment.