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

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.

Endocytic Adaptor Proteins in Health and Disease: Lessons from Model Organisms and Human Mutations

“…Besides, by impacting the sorting of different VAMPs CALM could also indirectly affect the trafficking itineraries, processing and degradation of proteins relevant for Alzheimer's disease [123]. Finally, in yeast and C. elegans CALM was able to reduce Aβ oligomerization by an enigmatic mechanism [132,133]. It is presently unclear whether all these suggested Alzheimer's disease relevant functions of neuronal CALM actually contribute equally to its effect on Alzheimer's disease and whether the neuronal and endothelial effects of CALM are both protective or rather at odds.…”

Calcium-responsive transactivator (CREST) toxicity is rescued by loss of PBP1/ATXN2 function in a novel yeast proteinopathy model and in transgenic flies

“…These yeast models have allowed the identification of yeast genes that either alter the disease protein's aggregation or enhance or reduce its toxicity. Remarkably, human homologs of these yeast modifier genes have confirmed (PICALM for Alzheimer's [38][39][40], PARK9 for Parkinson [38,41]), and identified new (ATXN2 [42][43][44][45][46] for ALS and XPO1, ADSSL1 and RABGEF1 for Alzheimer's [38,40]), human risk factors for the modeled disease. Indeed, the discovery in yeast that deletion of the ATXN2 (Ataxin-2) ortholog, PBP1, reduced TDP-43 toxicity, led to the recent exciting finding that reduction in ATXN2 levels dramatically lowers neurotoxicity in ALS mouse models [43].…”

Yeast screening platform identifies FDA-approved drugs that reduce Aβ oligomerization

“…Recently, Park and colleagues working in Susan Liebman’s group discovered a number of small molecules capable of modulating Aβ aggregation in a yeast model 28. The group constructed an Aβ fused to a translation factor domain to assess the Aβ oligomerization with a simple growth assay 29.…”

“…Park et al . screened 1200 FDA-approved drugs for the effect on Aβ oligomerization using a novel approach developed by the group earlier 28. The study uncovered 7 well-known compounds able to reduce oligomerization and rescue cellular toxicity in yeast (Fig.…”

“…The molecules identified by the Liebman group show promise in that their molecular mechanism seems to involve modulating the small oligomers, thought to be the toxic species in the long chain of events leading to Aβ toxicity in the brain 28. All of the molecules identified have already been approved by the FDA for use in humans, significantly accelerating any potential drug-to-market timeline.…”