Functional Links Between Ab Toxicity, Endocytic Trafficking, and Alzheimer’s Disease Risk Factors in Yeast

Ab (beta-amyloid peptide) is an important contributor to Alzheimer’s disease (AD). We modeled Ab toxicity in yeast by directing the peptide to the secretory pathway. A genome-wide screen for toxicity modifiers identified the yeast homolog of phosphatidylinositol binding clathrin assembly protein (PICALM) and other endocytic factors connected to AD whose relationship to Ab was previously unknown. The factors identified in yeast modified Ab toxicity in glutamatergic neurons of Caenorhabditis elegans and in primary rat cortical neurons. In yeast, Ab impaired the endocytic trafficking of a plasma membrane receptor, which was ameliorated by endocytic pathway factors identified in the yeast screen. Thus, links between Ab, endocytosis, and human AD risk factors can be ascertained with yeast as a model system. Yeast cells lack the specialized processesof neuronal cells and the cell-cell com-munications that modulate neuropathol-ogy. However, the most fundamental features of eukaryotic cell biology evolved before the split between yeast and metazoans. Yeast studies of the cell cycle, DNA damage repair, and check-points produced pivotal advances in cancer bi