Tenebrio molitor beetles have been widely used in traditional and folklore medicines to treat various human diseases worldwide. Alzheimer’s disease (AD) is a neurodegenerative disorder and the most prevalent form of dementia in developed and developing countries. The human β-amyloid cleaving enzyme (BACE-1) is a target for AD treatments. This study was performed to determine BACE-1 inhibitory activity of 12 compounds that were extracted from T. molitor adults and their 65 related compounds using a fluorescence resonance energy transfer-based enzyme assay. The results were compared with those of two positive controls for BACE-1, the cell-permeable isophthalamide BACE-1 inhibitor IV and the natural BACE-1 inhibitor, epigallocatechin gallate (EGCG). Based on IC50 values, linoleic acid, ergosterol, palmitoleic acid, and tryptopol (28.41‒46.16 μM) were the most potent BACE-1 inhibitors and the anti-BACE-1 activity of these compounds was lower than either inhibitor IV (13.13 μM) or EGCG (1.12 μM). Multiple regression analysis of the anti-BACE-1 activities of compounds was examined using their IC50 values and the values of the physical parameters (molecular weight (MW), log P, and molecular refraction (MR)) for the 41 fatty acids (R2 = 0.674 (P = 0.044)) and 29 flavonoids (R2 = 0.587 (P = 0.063)). Correlation coefficient (r) analysis showed that MW, log P, and MR may be positively correlated with IC50 of the fatty acids (MW, r = 0.658; log P, r = 0.471; and MR, r = 0.713) and IC50 of the flavonoids (MW, r = 0.547; log P, r = 0.644; and MR, r = 0.591). Further studies will warrant possible applications of T. molitor adults as therapeutic BACE-1 blocker.

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.