Curcumin Attenuates Arnyloid-β Aggregate Toxicity and Modulates Amyloid-β Aggregation Pathway

The abnormal misfolding and aggregation of amyloid-beta (A beta) peptides into beta-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 A beta 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 A beta 40 as well as A beta 40 aggregate induced neurotoxicity. Our results show that the curcumin does not inhibit A beta 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 A beta conformers, including monomeric, oligomeric, prefibrillar, and fibrillar A beta. The neuroprotective effect is possibly membrane-mediated, as curcumin reduced the extent of cell membrane permeabilization induced by A beta aggregates. Taken together, our study shows that curcumin exerts its neuroprotective effect against A beta induced toxicity through at least two concerted pathways, modifying the A beta aggregation pathway toward the formation of nontoxic aggregates and ameliorating A beta-induced toxicity possibly through a nonspecific pathway.