Curcumin Attenuates Amyloid-ß Aggregate Toxicity and Modulates Amyloid-ß Aggregation Pathway.

ABSTRACT

The abnormal misfolding and aggregation of amyloid-ß (Aß) peptides into ß-sheet enriched insoluble deposits initiates a cascade of events leading to pathological processes and culminating in cognitive decline in Alzheimer's disease (AD). In particular, soluble oligomeric/prefibrillar Aß have been shown to be potent neurotoxins. The naturally occurring polyphenol curcumin has been shown to exert a neuroprotective effect against age-related neurodegenerative diseases such as AD. However, its protective mechanism remains unclear. In this study, we investigated the effects of curcumin on the aggregation of Aß40 as well as Aß40 aggregate induced neurotoxicity. Our results show that the curcumin does not inhibit Aß fibril formation, but rather enriches the population of "off-pathway" soluble oligomers and prefibrillar aggregates that were nontoxic. Curcumin also exerted a nonspecific neuroprotective effect, reducing toxicities induced by a range of Aß conformers, including monomeric, oligomeric, prefibrillar, and fibrillar Aß. The neuroprotective effect is possibly membrane-mediated, as curcumin reduced the extent of cell membrane permeabilization induced by Aß aggregates. Taken together, our study shows that curcumin exerts its neuroprotective effect against Aß induced toxicity through at least two concerted pathways, modifying the Aß aggregation pathway toward the formation of nontoxic aggregates and ameliorating Aß-induced toxicity possibly through a nonspecific pathway.