(228ea) Elucidating the Neuroprotective Mechanism of Curcumin Against Amyloid Beta-Induced Toxicity in Alzheimer’s Disease

Alzheimerâ??s disease is the most prevalent form of dementia with 5.2 million people affected in the U.S. This neurodegenerative disease is characterized by the aggregation of the amyloid-beta (Aβ) protein into extracellular senile plaques. The aggregation mechanism and toxicity pathway of this protein is not well understood yet. However, its capability to bind directly to cell membrane could mediate both processes. Aβ binding to lipid membrane has been shown to seed aggregation and disrupt the lipid membrane.

We have previously shown that the polyphenolic compound, curcumin, reduces the Aβ toxicity by attenuating Aβ-lipid membrane interactions. Additionally, curcumin can directly reduce the toxicity of Aβ oligomers and modify the Aβ aggregation pathway. However, the detailed mechanisms by which curcumin affects Aβ toxicity and aggregation are still unknown.

In this study, we investigate the effect of curcumin on the aggregation of Aβ by monitoring the kinetics and morphology of Aβ oligomers and fibrils formed in presence of curcumin using a combination of characterization methods, including Thioflavin T (ThT) assay, size exclusion HPLC, Transmission Electron Microscopy (TEM) imaging, and dynamic light scattering. In particular, curcumin binding to oligomers and fibrils will be assessed. Finally, the effect of curcumin on Aβ aggregate toxicity will be tested. Results so far show that the presence of curcumin does not reduce protein aggregation and instead leads to increased levels of oligomeric and fibrillary forms of the protein. Additionally, a significant reduction of the Aβ toxicity was observed when the protein was incubated with curcumin.

Investigations are currently on going to determine whether a direct binding between curcumin and Aβ oligomers is leading to the reduction of oligomer toxicity. We propose to verify this interaction by monitoring the fluorescence of curcumin. We will also test the effect of curcumin on Aβ aggregate interaction with the lipid membrane by performing insertion assays of the Aβ aggregation-curcumin complex into lipid monolayers using a Langmuir Trough. This investigation will lead to a better understanding of the molecular mechanism(s) of curcuminâ??s inhibition of Aβ toxicity, which will contribute towards the development of therapeutic approaches to prevent or treat Alzheimerâ??s disease.