Alzheimer's (AD) and the Lewy body diseases (LBD; a family of diseases that includes Parkinson's) are the most common neurodegenerative disorders that appear to be caused by protein deposition. In AD, the amyloid beta peptide (Abeta) forms extracellular deposits, whereas in LBD, alpha-synuclein forms intracellular deposits. While it is clear that familial disease mutations hasten AD or LBD onset by making Abeta or alpha-synuclein more aggregation prone, this only accounts for a minority of AD and LBD cases. Most AD and LBD cases are sporadic (not associated with known mutations), and it is not clear why some individuals develop sporadic; AD or LBD while others do not. Known risk factors, such as hypercholesterolemia and inflammation, suggest a pathogenic mechanism for sporadic AD and LBD. Reactive oxygen species produced during inflammation can convert normal metabolites into aberrant, reactive metabolites, which can, in turn, accelerate AD or LBD onset by covalently modifying Abeta or alpha-synuclein. Preliminary results outlined within demonstrate that aberrant metabolites that possess aldehydes attached to large hydrophobic moieties, can covalently modify Abeta and alpha-synuclein, thus making them more aggregation prone. Herein, experiments are proposed to test the hypothesis that metabolite modification enhances aggregation by Abeta and alpha-synuclein by changing the aggregation mechanism. Techniques involving simple kinetic tests, selective dye binding, fluorescence correlation spectroscopy, and cell-based assays will be employed. Many of these experiments are designed specifically to overcome the technical challenges associated with studying the behavior of Abeta at physiological (nanomolar) concentrations. Characterizing the species and pathways involved in metabolite-initiated protein misfolding could lead to novel therapeutic strategies to target these diseases of growing impact.
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