In contrast to genetic lesions, epigenetic alterations are potentially reversible, thus holding promise for therapeutic intervention

a drug candidate for AD. The dominating view is that curcumin is an aggregation inhibitor, but recent studies of curcumin have shown that while it inhibits the oligomeric forms of Ab, it accelerates the formation of Ab fibrils. Curcumin is a potent binder of amyloid deposits, making it a molecular candidate for histological staining in pathology, and it has been suggested as a useful derivate in combination with near-infrared imaging in living subjects. In addition to these results, curcumin has also shown effects, mainly due to its anti-inflammatory properties, on other diseases such as rheumatoid arthritis, pancreatitis, cancer, osteoarthritis, and in some ocular as well as gastrointestinal conditions, such as ulcerative colitis. Current drug development strategies include development of curcumin analogues with similar biological XAV-939 site activity as curcumin, but with improved pharmacokinetic characteristics, including increased bioavailability and water solubility. Amyloidogenic proteins are known to be able to assemble into multiple forms of amyloid-like structures in vitro in a process known as “amyloid fibril polymorphism” suggesting that several mechanisms may be involved in amyloid formation. Multiple fibrillation pathways will probably result in multiple forms of preFebruary 2012 | Volume 7 | Issue 2 | e31424 Reduced Neurotoxicity by Promoted Fibrillation fibrillary species, responsible for toxicity. The connection between these complex folding processes and curcumin is not clear. Here, we have addressed the potency of curcumin in alleviating AD-like symptoms in transgenic Drosophila models of AD. To this end we used four different Ab expressing Drosophila lines , and one human Tau expressing Drosophila line, all expressed in the Drosophila central nervous system and eyes by the Gal4/UAS system. The longevity and the locomotor activity of the different genotypes were measured relative to a control line. To detect amyloid formation ex vivo, we combined antibody staining with a luminescent conjugated oligothiophene, p-FTAA, as a marker for amyloid, and collected structural dependent spectra from the probe for different time points as the aggregation accelerates in the tissue. These results, combined with in vitro fibrillation of recombinant Ab and quantification of the soluble and insoluble Ab produced in the flies in ” absence or presence of curcumin, shows that curcumin does not inhibit amyloid formation. On the contrary, curcumin rather accelerates amyloid fibril conversion, and hence reduce the pre-fibrillary species of Ab. This suggests that the reduction of pre-fibrillar species underlies the observed mitigated neurotoxicity in Drosophila. Results Drosophila longevity To address the effects of curcumin upon AD-related symptoms in Drosophila, we initially fed various concentrations of curcumin to the control flies. Rather unexpectedly, this however rendered a reduced lifespan. The reduced viability was curcumin concentration dependent, resulting in a decreased median survival time . The Ab140 expressing flies showed a decreased T1/2 compared to the control flies, 15456246” and was only affected by the higher curcumin concentrations, also here resulting in a decreased life span. For the low concentration of curcumin, the lifespan was unaffected. Curcumin feeding of the single inserted Ab142 expressing flies showed a positive effect of the T1/2 at low and intermediate curcumin concentrations and no effect of the T1/2 on the highest curcumin conce