Abstract
The human β-amyloid (Aβ) cleaving enzyme (BACE-1) is a target for Alzheimer’s disease (AD) treatments. This study was conducted to determine if acacetin extracted from the whole Agastache rugosa plant had anti-BACE-1 and behavioral activities in Drosophila melanogaster AD models and to determine acacetin’s mechanism of action. Acacetin (100, 300, and 500 μM) rescued amyloid precursor protein (APP)/BACE1-expressing flies and kept them from developing both eye morphology (dark deposits, ommatidial collapse and fusion, and the absence of ommatidial bristles) and behavioral (motor abnormalities) defects. The reverse transcription polymerase chain reaction analysis revealed that acacetin reduced both the human APP and BACE-1 mRNA levels in the transgenic flies, suggesting that it plays an important role in the transcriptional regulation of human BACE-1 and APP. Western blot analysis revealed that acacetin reduced Aβ production by interfering with BACE-1 activity and APP synthesis, resulting in a decrease in the levels of the APP carboxy-terminal fragments and the APP intracellular domain. Therefore, the protective effect of acacetin on Aβ production is mediated by transcriptional regulation of BACE-1 and APP, resulting in decreased APP protein expression and BACE-1 activity. Acacetin also inhibited APP synthesis, resulting in a decrease in the number of amyloid plaques.
Highlights
Amyloidogenic processing pathway, namely β -secretase (β -site amyloid precursor protein (APP) cleaving enzyme or BACE-1) and γ -secretase[5,6,7]
The fractions obtained from solvent partitioning of the methanol extract of the whole A. rugosa plant were tested for human BACE-1inhibitory activity using a fluorescence resonance energy transfer (FRET)-based enzyme assay (Table 1)
We investigated the effects of acacetin on the lifespan and T1/2 of our Drosophila Alzheimer’s disease (AD) model, because it was previously reported that co-expression of BACE-1 and APP reduced the lifespan of the adult flies[37]
Summary
Amyloidogenic processing pathway, namely β -secretase (β -site APP cleaving enzyme or BACE-1) and γ -secretase[5,6,7]. AD is currently treated using acetylcholinesterase (AChE) inhibitors[8] and N-methyl-D-aspartate (NMDA) receptor antagonists[9,10] These treatments do not stop the disease process or prevent neuronal degeneration[11]. Natural compounds from plant extracts have been suggested as alternative sources for anti-AD drugs. This approach is appealing, in part, because plants are sources of bioactive secondary metabolites that are perceived by the general public as relatively safe, and that often act on multiple, novel target sites[19,20]. Kuntze (Lamiaceae), possessed human BACE-1 inhibitory activity This plant species has been used to treat cholera, vomiting, and miasma[22]. The possible mechanism underlying the anti-AD actions of acacetin was elucidated using real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blot analyses
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