Abstract
Aβ (beta-amyloid peptide) is an important contributor to Alzheimer's disease (AD). We modeled Aβ 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 Aβ was previously unknown. The factors identified in yeast modified Aβ toxicity in glutamatergic neurons of Caenorhabditis elegans and in primary rat cortical neurons. In yeast, Aβ impaired the endocytic trafficking of a plasma membrane receptor, which was ameliorated by endocytic pathway factors identified in the yeast screen. Thus, links between Aβ, endocytosis, and human AD risk factors can be ascertained with yeast as a model system.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Alzheimer Disease / genetics*
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Alzheimer Disease / metabolism*
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Amyloid beta-Peptides / chemistry
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Amyloid beta-Peptides / genetics
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Amyloid beta-Peptides / metabolism*
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Animals
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Animals, Genetically Modified
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Caenorhabditis elegans / cytology
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Caenorhabditis elegans / genetics
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Caenorhabditis elegans / metabolism
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Cell Membrane / metabolism
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Cells, Cultured
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Clathrin / metabolism
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Cytoskeleton / metabolism
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Disease Susceptibility
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Endocytosis*
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Genetic Association Studies
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Genetic Testing
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Glutamates / metabolism
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Humans
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Monomeric Clathrin Assembly Proteins / genetics
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Monomeric Clathrin Assembly Proteins / metabolism
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Neurons / physiology
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Peptide Fragments / chemistry
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Peptide Fragments / genetics
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Peptide Fragments / metabolism*
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Protein Multimerization
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Protein Transport
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Rats
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Risk Factors
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Saccharomyces cerevisiae Proteins / genetics
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Saccharomyces cerevisiae Proteins / metabolism
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Saccharomyces cerevisiae* / cytology
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Saccharomyces cerevisiae* / genetics
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Saccharomyces cerevisiae* / growth & development
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Saccharomyces cerevisiae* / metabolism
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Secretory Pathway
Substances
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Amyloid beta-Peptides
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Clathrin
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Glutamates
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Monomeric Clathrin Assembly Proteins
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PICALM protein, human
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Peptide Fragments
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Saccharomyces cerevisiae Proteins
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amyloid beta-protein (1-42)