Alzheimer’s disease (AD) is the most common type of presenile and senile dementia. Human β-amyloid precursor cleavage enzyme (BACE-1) is a key enzyme responsible for amyloid plaque production. We assessed anti-BACE-1 and behavioral activities of curcuminoids from Curcuma longa, curcumin (CCN), demethoxycurcumin (DMCCN), and bisdemethoxycurcumin (BDMCCN) against AD fly models. Neuro-protective ability of curcuminoids was assessed using fly model system overexpressing BACE-1 and its substrate APP in compound eyes and entire neurons. BDMCCN has the strongest inhibitory activity toward BACE-1 with 17 μM IC50, which was 20 and 13 times lower than those of CCN and DMCCN respectively. Expression of APP/BACE-1 resulted in the progressive and measurable defects in morphology of eyes and locomotion. Supplementing diet with either 1 mM BDMCCN or CCN rescued APP/BACE1 expressing flies and kept them from developing both morphological and behavioral defects. Structural characteristics and hydrophobicity appear to play a role in determining inhibitory potency of curcuminoids on BACE-1.

An assessment was made of beta-site amyloid precursor protein (APP) cleaving enzyme (BACE1) inhibitory, feeding, climbing activities and lifespan of the diarylalkyls curcumin (CCN), demethoxycurcumin (DCCN) and bisdemethoxycurcumin (BDCCN) identified in the rhizomes of Curcuma longa. Based on IC50 values, BDCCN (0.024 mM) was the most inhibitory constituent, followed by DCCN (0.31 mM) and CCN (0.59 mM). Overall the three curcuminoids were significantly less inhibitory than BACE1 inhibitor IV isophthalamide (8.5 × 10-5 mM). The expression of human APP and BACE1 in compound eye of Drosophila melangaster presented rough abnormal ommatidial lattice. Co-expression of APP and BACE1 within the developing nervous system of drosophila showed climbing defects. These transgenic flies kept on media containing 1 mM of CCN and BDCCN were observed to ameliorate eye degeneration, significantly suppress locomotive dysfunctions, and increase media life time, as well as isophthalamide. CCN and BDCCN as human BACE1 inhibitory constituents may be used as potential therapeutics or lead molecules to develop Alzheimer's disease treatment drugs.