Development and validation of a humanized yeast model for Abeta42-induced cytotoxicity

Alzheimer’s Disease (AD) is the most common neurodegenerative disorder. Today, more than 25 million people are suffering from AD, a number that has been estimated to double every 20 years. Brains from AD patients have two major hallmarks. They contain intracellular deposits of hyperphosphorylated protein tau, known as neurofibrillary tangles, as well as extracellular deposits of Aβ peptides, known as amyloid plaques. The latter are derived from cleavage of the amyloid precursor protein by the β- and gamma-secretases. Despite enormous efforts, the exact molecular mechanisms underlying the pathology and neuronal loss in AD brain are still not known. According to a current hypothesis, the accumulation of intracellular oligomeric complexes of Aβ-peptides induces cytotoxicity and cellular stress, which in turn activates stress-sensitive kinases that hyper-phosphorylate and induce aggregation of protein tau. In our project, we aim to develop a humanized yeast model to investigate Aβ-induced toxicity and its causal effect on the behavior of protein tau in the unicellular eukaryote Saccharomyces cerevisiae or baker’s yeast, a strategy already successfully applied to decipher the toxicity mechanisms for other proteins triggering neurodegeneration in e.g. Parkinson’s and Huntington’s disease. Preliminary data shows that the proteasome plays an important role in clearing Aβ42, as severe growth defects are observed in proteasomally-impaired strains.status: publishe