This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. A pathological hallmark of Alzheimer s Disease (AD) is the accumulation of aggregated amyloid-beta peptides (A ) in senile plaques within the brain. A 1-42, the predominant peptide found in senile plaques, has a striking propensity to self-aggregate into a -pleated sheet conformation to form fibrillar amyloid (fA ). Compact senile plaques are comprised of dense aggregates of fA ; this accumulation is widely believed to be a fundamental event in the pathogenesis of AD, initiating a cascade of deleterious process including the induction of oxidative stress, inflammation, and neurotoxicity. Studies over the last decade have suggested that polyphenols, natural substances with variable phenolic structures found in various health foods, possess potent antioxidant properties and appear to play a role in the prevention of a variety of diseases. Several groups have recently found that some polyphenols are capable of inhibiting the aggregation of synthetic A into fibrils and oligomers in vitro. The best studied, curcumin, the active ingredient in tumeric a spice used in curry (the incidence of AD in India is that in the US), inhibited the fibrilization of A as detected by thioflavine-T (ThT) fluorescence, and transmission electron microscopy (TEM). Furthermore, an AD mouse model (Tg2576 mice) fed curcumin from 17 to 22 months of age had decreased amyloid plaque burden compared to untreated mice, suggesting an effect on plaque pathogenesis. A host of other polyphenols (including tannic acid, myricetin, morin, ferulic acid, amongst others) has also been shown to demonstrate anti-amyloidogenic activity in vitro. While the primary focus has been on the inhibition of A aggregation, preliminary but indirect evidence suggests that polyphenols may promote amyloid fibril disaggregation in vitro. This distinction between the inhibition of aggregation and disaggregation is important because of its implications for disease arrest vs. reversal. We propose to use cryo-electron microscopy (cryo-EM) to determine if curcumin induces changes in the structure of the amyloid fibril. Previous reports have demonstrated that synthetic amyloid fibrils can be directly visualized using cryo-EM, and reveal a -sheet structure that is observable as striations across the fibers (though fibrils formed from A 11-25 had better imaging characteristics than A 1-42). Amyloid fibrils will be imaged using cryo-EM in the presence or absence of curcumin (at varying times after addition), and with Congo Red, which binds but does not induce fibril disaggregation. Image analysis will include measurements of fibril diameter, distance between striations (representing distance between -sheets), and the pitch of protofilament wrapping. We also propose to use cryo-EM to further characterize breakdown products of curcumin incubation.
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