Inhibition of Aβ42 oligomerization in yeast by a PICALM ortholog and certain FDA approved drugs
The formation of small Aβ 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), redu...
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Veröffentlicht in: | Microbial cell 2016-02, Vol.3 (2), p.53-64 |
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Zusammenfassung: | The formation of small Aβ
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 Aβ
42
fused to a reporter in yeast. Thus we used
the Aβ
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
Aβ
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 Aβ
42
to be less toxic to PC12 cells and to relieve toxicity of another yeast AD model
in which Aβ
42
aggregates targeted to the secretory pathway are toxic.
Our results identify drugs that inhibit Aβ
42
oligomers from forming
in yeast. It remains to be determined if these drugs inhibit Aβ
42
oligomerization in mammals and could be developed as a therapeutic treatment for
AD. |
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ISSN: | 2311-2638 2311-2638 |
DOI: | 10.15698/mic2016.02.476 |