(157d) Curcumin Attenuates Amyloid Beta Peptide Toxicity by Forming off-Pathway Intermediates

Amyloid beta peptide (Aβ) aggregation plays a central role in the pathogenesis of Alzheimer’s disease (AD). Therefore, inhibition of Aβ aggregation using small molecule inhibitors is considered as an attractive therapeutic strategy to suppress AD. On the other hand, small molecules inhibitors of Aβ aggregation have been useful to categorize the distinct and complex processes of amyloid formation occurring in heterogeneous protein aggregation. A recent study on small molecule inhibitors of Aβ aggregation showed that polyphenolic antioxidant small molecule, curcumin, a previously known potent inhibitor of Aβ oligomerization/fibrilization and fibrils disrupting agent, inhibits Aβ oligomerization but not fibrilization. This finding also generated a doubt over the previously purposed mechanism(s) of some of the other potent anti-fibrillogenic small molecules to reduce Aβ toxicity. To understand how curcumin mediates cytoprotective effect by inhibiting oligomerization but not fibrilization, we analyzed the Aβ aggregates formed in the presence of curcumin by thioflavin-T assay, circular dichroism study and transmission electron microscopy and found that curcumin competes with thioflavin-T binding without influencing the fibril formation of Aβ40. Size-exclusion high performance chromatography (SE-HPLC) revealed that curcumin populates Aβ oligomers; presumably partially folded metastable off-pathway intermediates assembled in parallel with on-pathway fibril formation and stabilizes them to nontoxic conformations. Our data also show that curcumin is also effective against various toxic species of Aβ, including oligomers and fibrils though they may be distinctly different in sizes, structures, conformations and toxicities. Moreover, SE-HPLC fractionated curcumin accumulated Aβ intermediates demonstrate that these species modulate generic Aβ fibril formation to off-pathway by generating unusual protofibrillar-like assemblies. Taken together, our data suggest that curcumin captures the Aβ intermediates, most likely off-pathway assemblies, and transforms them into a nontoxic form without significantly altering on-pathway fibril formation.