Oral Presentation Australian Society for Microbiology Annual Scientific Meeting 2021

The use of budding yeast to gain insights into Alzheimer’s Disease and its prevention (#90)

Ian G Macreadie 1 , Sudip Dhakal 1 , Joshua M Fraser 1 , Ken Gardiner 1 , Mishal Subhan 1
  1. RMIT University, Bundoora, VIC, Australia

Ab, a proteolytic product derived from a normal cellular protein, may be the cause of Alzheimer’s disease.  As a result of declining proteostasis with age, Ab accumulates and can reach levels that may cause neuronal loss.  We have used budding yeast, to understand more about aging, clearance of Ab and to examine drugs that can prevent Alzheimer’s disease.  Budding yeast populations are good models of aging and are composed of 50% newly budded cells, 25% first time mothers, 12.5% second time mothers, and so on.  Reduced proteostasis is observed in 10-30% of the population which are the older cells that exhibit multiple bud scars and larger size.  Reduced proteostasis in aging can be directly visualized by constitutively expressing Ab fused to green fluorescent protein (Ab-GFP or GFP-Ab), which is cleared by the younger cells but not the oldest cells in the population.  We have utilized these yeast to screen for compounds that can clear Ab-GFP or GFP-Ab.  One of the best compounds, the cholesterol lowering drug, simvastatin, reduces most of the GFP-Ab, while the other statins have a weaker effect.  This result is especially encouraging since it corresponds with epidemiology studies that show a 50% reduction in Alzheimer’s disease for those taking simvastatin.  The effect appears to be unrelated to cholesterol reduction since the other statins do not exert a pronounced effect, and fluconazole, which targets the equivalent pathway, has no effect on proteostasis.  Simvastatin also clears native Ab from cells.  It therefore appears that simvastatin improves proteostasis.