Effects of curcuminoids identified in rhizomes of Curcuma longa on BACE-1 inhibitory and behavioral activity and lifespan of Alzheimer’s disease Drosophila models

Xue Wang,Hyung-Wook Kwon,Seong-Baek Lee,Jun-Ran Kim,Young-Joon Ahn,Young-Joon Kim,Moon Young Jung

doi:10.1186/1472-6882-14-88

Abstract

BackgroundAlzheimer’s disease (AD) is the most common type of presenile and senile dementia. The human β-amyloid precursor cleavage enzyme (BACE-1) is a key enzyme responsible for amyloid plaque production, which implicates the progress and symptoms of AD. Here we assessed the anti-BACE-1 and behavioral activities of curcuminoids from rhizomes of Curcuma longa (Zingiberaceae), diarylalkyls curcumin (CCN), demethoxycurcumin (DMCCN), and bisdemethoxycurcumin (BDMCCN) against AD Drosophila melanogaster models.MethodsNeuro-protective ability of the curcuminoids was assessed using Drosophila melanogaster model system overexpressing BACE-1 and its substrate APP in compound eyes and entire neurons. Feeding and climbing activity, lifespan, and morphostructural changes in fly eyes also were evaluated.ResultsBDMCCN 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. Overexpression of APP/BACE-1 resulted in the progressive and measurable defects in morphology of eyes and locomotion. Remarkably, supplementing diet with either 1 mM BDMCCN or 1 mM CCN rescued APP/BACE1-expressing flies and kept them from developing both morphological and behavioral defects. Our results suggest that structural characteristics, such as degrees of saturation, types of carbon skeleton and functional group, and hydrophobicity appear to play a role in determining inhibitory potency of curcuminoids on BACE-1.ConclusionFurther studies will warrant possible applications of curcuminoids as therapeutic BACE-1 blockers.

Highlights

Alzheimer’s disease (AD) is the most common type of presenile and senile dementia
GMR-Gal4 drives target human amyloid precursor protein (APP) and β-amyloid precursor cleavage enzyme (BACE-1) genes expression in flies’ compound eyes, and morphostructural changes of these compound eyes with the supplementation of compounds with different concentration were observed, GMR-Gal4/+ was used as the control group (Figure 1A), elav-Gal4 drives target genes coexpression in flies’ nervous system, behaviors including climbing, life span and feeding assay with the supplementation of compounds with different concentration were tested, elav-Gla4/+ and elav < BACE-1 were used as control groups (Figure 1B)
fluorescence resonance energy transfer (FRET) bioassay-guided fractionation and isolation of curcuminoids Fractions obtained from the solvent hydrolyzable of the methanol extract of C. longa rhizomes were examined for inhibitory activity against human BACE-1 using a FRET-based enzyme assay (Table 2)

Summary

Introduction

Alzheimer’s disease (AD) is the most common type of presenile and senile dementia. The human β-amyloid precursor cleavage enzyme (BACE-1) is a key enzyme responsible for amyloid plaque production, which implicates the progress and symptoms of AD. We assessed the anti-BACE-1 and behavioral activities of curcuminoids from rhizomes of Curcuma longa (Zingiberaceae), diarylalkyls curcumin (CCN), demethoxycurcumin (DMCCN), and bisdemethoxycurcumin (BDMCCN) against AD Drosophila melanogaster models. Plant secondary substances have been suggested as potential alternatives for AD therapy largely because plants constitute a potential source of bioactive chemicals that have been perceived by the general public as relatively safe and often act at multiple and novel target sites [14,15]. These potential new anti-AD products can be applied to humans in the same manner as conventional anti-AD drugs. An active ingredient of C. longa, has been proposed to alleviate Aβ toxicity in transgenic human Aβ and human tau flies by reducing the pre-fibrillar/oligomeric species of Aβ [18]

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