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Effects and possible mechanisms of action of acacetin on the behavior and eye morphology of Drosophila models of Alzheimer's disease.

Wang X, Perumalsamy H, Kwon HW, Na YE, Ahn YJ - Sci Rep (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Agricultural Biotechnology, Seoul National University, Seoul 151-921, Republic of Korea.

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.

No MeSH data available.


Related in: MedlinePlus

Structures of maslinic acid, oleanolic acid, and acacetin.These compounds were identified in the whole Agastache rugosa plants in this study. The chemical formula of maslinic acid (1) is C30H48O4, with a molar mass of 472.70 g/mol; the chemical formula of oleanolic acid (2) is C30H48O3, with a molar mass of 456.70 g/mol; and the chemical formula of acacetin (3) is C16H12O5, with a molar mass of 284.26 g/mol.
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f1: Structures of maslinic acid, oleanolic acid, and acacetin.These compounds were identified in the whole Agastache rugosa plants in this study. The chemical formula of maslinic acid (1) is C30H48O4, with a molar mass of 472.70 g/mol; the chemical formula of oleanolic acid (2) is C30H48O3, with a molar mass of 456.70 g/mol; and the chemical formula of acacetin (3) is C16H12O5, with a molar mass of 284.26 g/mol.

Mentions: FRET-based enzyme assay-guided fractionation of the whole A. rugosa plant afforded three active compounds that were identified by spectroscopic analyses, including electron ionized mass spectrometry (EI-MS) and nuclear magnetic resonance (NMR) spectroscopy. The three BACE-1 inhibitory compounds were maslinic acid (1), oleanolic acid (2), and acacetin (3) (Fig. 1). Maslinic acid (1) was identified based on the following evidence: a white crystal; Ultraviolet (UV) (MeOH): λmax nm = 217; EI-MS (70 eV), m/z (% relative intensity): 472 [M]+ (1.9), 284 (3.0), 256 (2.8), 248 (100), 233 (8.6), 203 (73.5), 189 (8.1), 173 (3.4), 133 (10.2), 105 (5.1), 95 (4.4), 69 (6.2), 55 (5.3) (see Supplementary Fig. S1 online); 1H NMR (MeOD, 600 MHz): δ 0.79 (3H, s), 0.86 (3H, s), 0.87 (3H, s), 0.94 (3H, s), 0.99 (3H, s), 1.10 (3H, s), 1.13 (3H, s), 2.89 (1H, m), 2.98 (1H, d, J = 9.54 Hz), 3.61 (1H, ddd, J = 4.50, 2.94, 3.90 Hz), 5.21 (1H, t, J = 6.72 Hz) (see Supplementary Fig. S2 online); and 13C NMR (MeOD, 150 MHz): δ 17.2 q, 17.6 q, 18.3 q, 19.8 t, 24.5 q, 24.7 q, 24.8 t, 26.6 t, 29.4 t, 29.5 q, 30.9 s, 31.9 q, 34.1 t, 34.2 t, 34.5 t, 39.5 s, 40.6 s, 40.7 s, 43.2 s, 43.8 d, 48.3 t, 48.4 s, 48.7 t, 49.0 d, 56.9 d, 69.7 d, 84.7 d, 122.5 d, 146.9 s, 185.8 s (see Supplementary Fig. S3 online). Oleanolic acid (2) was characterized as follows: a white amorphous powder; UV (MeOH): λmax nm = 216; EI-MS (70 eV), m/z (% relative intensity): 456 [M]+ (4.3), 249 (18.8), 248 (100), 233 (6.0), 207 (17.3), 204 (11.3), 203 (59.7), 190 (10.0), 189 (10.6), 175 (7.4), 133 (15.0), 105 (6.7), 81 (6.1), 69 (8.0), 55 (7.6) (see Supplementary Fig. S4 online); 1H NMR (MeOD, 600 MHz): δ 0.77 (3H, s), 0.85 (3H, s), 0.90 (3H, s), 0.95 (3H, s), 0.97 (3H, s), 1.12 (3H, s), 1.15 (3H, s). 1.38 (2H, m), 1.41 (2H, m), 1.56 (4H, m), 2.20 (3H, m), 2.85 (1H, dd, J = 9.9, 4.5 Hz), 3.15 (1H, dd, J = 15.78, 4.4 Hz), 3.17 (1H, t, J = 14.76 Hz), 3.34 (2H, s), 4.62 (2H, s), 5.23 (1H, s) (see Supplementary Fig. S5 online); and 13C NMR (MeOD, 150 MHz): δ 16.0 q, 16.5 q, 16.5 q, 17.9 t, 21.7 t, 24.2 q, 24.3 t, 25.5 q, 26.5 t, 28.0 t, 28.9 q, 31.8 s, 33.8 t, 34.0 t, 34.2 q, 34.5 t, 35.1 s, 38.2 t, 38.3 s, 40.0 s, 40.7 d, 42.9 s, 43.0 s, 47.5 t, 47.9 d, 56.9 d, 79.8 d, 123.7 d, 145.5 s, 182.4 s (see Supplementary Fig. S6 online). Acacetin (3) was characterized as follows: yellow needles; UV (MeOH): λmax nm = 269, 315; EI-MS (70 eV), m/z (% relative intensity): 284 [M]+ (100), 283 (12.5), 241 (11.4), 152 (6.9), 132 (18) (see Supplementary Fig. S7 online); High resolution EI-MS: C16H12O5 observed: 284.0683, calculated: 284.0684; Fourier transform infrared spectroscopy (FT-IR) νmax cm–1: 3147 (-OH), 1651 (−C=O), 1605, 1560, 1503, 1428 (-C=C) (see Supplementary Fig. S8 online); 1H NMR (DMSO-d6, 600 MHz): δ 3.16 (3H, s), 6.20 (1H, d, J = 1.98 Hz), 6.51 (1H, d, J = 2.04 Hz), 6.87 (1H, s), 7.11 (2H, d, J = 8.88 Hz), 8.04 (2H, d, J = 8.88 Hz), 10.85 (1H, s), 12.92 (1H, s) (see Supplementary Fig. S9 online); and 13C NMR (DMSO-d6, 150 MHz): δ 55. 6 q, 94.0 d, 98.9 d, 103.5 d, 103.8 s, 114.6 d, 114.6 d, 122. 8 s, 128.3 d, 128.3 d, 157.3 s, 161.4 s, 162.3 s, 163.3 s, 164.2 s, 181.8 s (see Supplementary Fig. S10 online). The interpretations of the proton and carbon signals of compounds 1, 2, and 3 were largely consistent with those of Tanaka et al.25 and Dam et al.26, Hossain and Ismail27 and Gangwal et al.28, and Wawer and Zielinska29 and Miyazawa and Hisama30, respectively.


Effects and possible mechanisms of action of acacetin on the behavior and eye morphology of Drosophila models of Alzheimer's disease.

Wang X, Perumalsamy H, Kwon HW, Na YE, Ahn YJ - Sci Rep (2015)

Structures of maslinic acid, oleanolic acid, and acacetin.These compounds were identified in the whole Agastache rugosa plants in this study. The chemical formula of maslinic acid (1) is C30H48O4, with a molar mass of 472.70 g/mol; the chemical formula of oleanolic acid (2) is C30H48O3, with a molar mass of 456.70 g/mol; and the chemical formula of acacetin (3) is C16H12O5, with a molar mass of 284.26 g/mol.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4632086&req=5

f1: Structures of maslinic acid, oleanolic acid, and acacetin.These compounds were identified in the whole Agastache rugosa plants in this study. The chemical formula of maslinic acid (1) is C30H48O4, with a molar mass of 472.70 g/mol; the chemical formula of oleanolic acid (2) is C30H48O3, with a molar mass of 456.70 g/mol; and the chemical formula of acacetin (3) is C16H12O5, with a molar mass of 284.26 g/mol.
Mentions: FRET-based enzyme assay-guided fractionation of the whole A. rugosa plant afforded three active compounds that were identified by spectroscopic analyses, including electron ionized mass spectrometry (EI-MS) and nuclear magnetic resonance (NMR) spectroscopy. The three BACE-1 inhibitory compounds were maslinic acid (1), oleanolic acid (2), and acacetin (3) (Fig. 1). Maslinic acid (1) was identified based on the following evidence: a white crystal; Ultraviolet (UV) (MeOH): λmax nm = 217; EI-MS (70 eV), m/z (% relative intensity): 472 [M]+ (1.9), 284 (3.0), 256 (2.8), 248 (100), 233 (8.6), 203 (73.5), 189 (8.1), 173 (3.4), 133 (10.2), 105 (5.1), 95 (4.4), 69 (6.2), 55 (5.3) (see Supplementary Fig. S1 online); 1H NMR (MeOD, 600 MHz): δ 0.79 (3H, s), 0.86 (3H, s), 0.87 (3H, s), 0.94 (3H, s), 0.99 (3H, s), 1.10 (3H, s), 1.13 (3H, s), 2.89 (1H, m), 2.98 (1H, d, J = 9.54 Hz), 3.61 (1H, ddd, J = 4.50, 2.94, 3.90 Hz), 5.21 (1H, t, J = 6.72 Hz) (see Supplementary Fig. S2 online); and 13C NMR (MeOD, 150 MHz): δ 17.2 q, 17.6 q, 18.3 q, 19.8 t, 24.5 q, 24.7 q, 24.8 t, 26.6 t, 29.4 t, 29.5 q, 30.9 s, 31.9 q, 34.1 t, 34.2 t, 34.5 t, 39.5 s, 40.6 s, 40.7 s, 43.2 s, 43.8 d, 48.3 t, 48.4 s, 48.7 t, 49.0 d, 56.9 d, 69.7 d, 84.7 d, 122.5 d, 146.9 s, 185.8 s (see Supplementary Fig. S3 online). Oleanolic acid (2) was characterized as follows: a white amorphous powder; UV (MeOH): λmax nm = 216; EI-MS (70 eV), m/z (% relative intensity): 456 [M]+ (4.3), 249 (18.8), 248 (100), 233 (6.0), 207 (17.3), 204 (11.3), 203 (59.7), 190 (10.0), 189 (10.6), 175 (7.4), 133 (15.0), 105 (6.7), 81 (6.1), 69 (8.0), 55 (7.6) (see Supplementary Fig. S4 online); 1H NMR (MeOD, 600 MHz): δ 0.77 (3H, s), 0.85 (3H, s), 0.90 (3H, s), 0.95 (3H, s), 0.97 (3H, s), 1.12 (3H, s), 1.15 (3H, s). 1.38 (2H, m), 1.41 (2H, m), 1.56 (4H, m), 2.20 (3H, m), 2.85 (1H, dd, J = 9.9, 4.5 Hz), 3.15 (1H, dd, J = 15.78, 4.4 Hz), 3.17 (1H, t, J = 14.76 Hz), 3.34 (2H, s), 4.62 (2H, s), 5.23 (1H, s) (see Supplementary Fig. S5 online); and 13C NMR (MeOD, 150 MHz): δ 16.0 q, 16.5 q, 16.5 q, 17.9 t, 21.7 t, 24.2 q, 24.3 t, 25.5 q, 26.5 t, 28.0 t, 28.9 q, 31.8 s, 33.8 t, 34.0 t, 34.2 q, 34.5 t, 35.1 s, 38.2 t, 38.3 s, 40.0 s, 40.7 d, 42.9 s, 43.0 s, 47.5 t, 47.9 d, 56.9 d, 79.8 d, 123.7 d, 145.5 s, 182.4 s (see Supplementary Fig. S6 online). Acacetin (3) was characterized as follows: yellow needles; UV (MeOH): λmax nm = 269, 315; EI-MS (70 eV), m/z (% relative intensity): 284 [M]+ (100), 283 (12.5), 241 (11.4), 152 (6.9), 132 (18) (see Supplementary Fig. S7 online); High resolution EI-MS: C16H12O5 observed: 284.0683, calculated: 284.0684; Fourier transform infrared spectroscopy (FT-IR) νmax cm–1: 3147 (-OH), 1651 (−C=O), 1605, 1560, 1503, 1428 (-C=C) (see Supplementary Fig. S8 online); 1H NMR (DMSO-d6, 600 MHz): δ 3.16 (3H, s), 6.20 (1H, d, J = 1.98 Hz), 6.51 (1H, d, J = 2.04 Hz), 6.87 (1H, s), 7.11 (2H, d, J = 8.88 Hz), 8.04 (2H, d, J = 8.88 Hz), 10.85 (1H, s), 12.92 (1H, s) (see Supplementary Fig. S9 online); and 13C NMR (DMSO-d6, 150 MHz): δ 55. 6 q, 94.0 d, 98.9 d, 103.5 d, 103.8 s, 114.6 d, 114.6 d, 122. 8 s, 128.3 d, 128.3 d, 157.3 s, 161.4 s, 162.3 s, 163.3 s, 164.2 s, 181.8 s (see Supplementary Fig. S10 online). The interpretations of the proton and carbon signals of compounds 1, 2, and 3 were largely consistent with those of Tanaka et al.25 and Dam et al.26, Hossain and Ismail27 and Gangwal et al.28, and Wawer and Zielinska29 and Miyazawa and Hisama30, respectively.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Agricultural Biotechnology, Seoul National University, Seoul 151-921, Republic of Korea.

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.

No MeSH data available.


Related in: MedlinePlus