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Aging and disease    2018, Vol. 9 Issue (4) : 605-622     DOI: 10.14336/AD.2017.0903
Orginal Article |
Neuroprotective Effect of Caffeic Acid Phenethyl Ester in A Mouse Model of Alzheimer’s Disease Involves Nrf2/HO-1 Pathway
Morroni Fabiana1,*, Sita Giulia1, Graziosi Agnese1, Turrini Eleonora2, Fimognari Carmela2, Tarozzi Andrea2, Hrelia Patrizia1
1Department of Pharmacy and Biotechnology, Alma Mater Studiorum, University of Bologna, Bologna, Italy
2Department for Life Quality Studies, Alma Mater Studiorum, University of Bologna, 47900 Rimini, Italy
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Abstract  

Alzheimer’s disease (AD) is a progressive pathology, where dementia symptoms gradually worsen over a number of years. The hallmarks of AD, such as amyloid β-peptide (Aβ) in senile plaque and neurofibrillary tangles, are strongly intertwined with oxidative stress, which is considered one of the common effectors of the cascade of degenerative events. The endogenous nuclear factor erythroid 2-related factor 2 (Nrf2) is the "master regulator" of the antioxidant response and it is known as an indicator and regulator of oxidative stress. The present study aimed to determine the potential neuroprotective activity of caffeic acid phenethyl ester (CAPE), a polyphenolic compound abundant in honeybee, against the neurotoxicity of Aβ1-42 oligomers (AβO) in mice. An intracerebroventricular (i.c.v.) injection of AβO into the mouse brain triggered increased reactive oxygen species levels, neurodegeneration, neuroinflammation, and memory impairment. In contrast, the intraperitoneal administration of CAPE (10 mg/kg) after i.c.v. AβO-injection counteracted oxidative stress accompanied by an induction of Nrf2 and heme oxygenase-1 via the modulation of glycogen synthase kinase 3β in the hippocampus of mice. Additionally, CAPE treatment decreased AβO-induced neuronal apoptosis and neuroinflammation, and improved learning and memory, protecting mice against the decline in spatial cognition. Our findings demonstrate that CAPE could potentially be considered as a promising neuroprotective agent against progressive neurodegenerative diseases such as AD.

Keywords caffeic acid phenethyl ester      neuroprotection      Aβ oligomers      Alzheimer’s disease      Nrf2      oxidative stress     
Corresponding Authors: Morroni Fabiana   
About author:

These authors contributed equally to this work.

Issue Date: 01 August 2018
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Morroni Fabiana
Sita Giulia
Graziosi Agnese
Turrini Eleonora
Fimognari Carmela
Tarozzi Andrea
Hrelia Patrizia
Cite this article:   
Morroni Fabiana,Sita Giulia,Graziosi Agnese, et al. Neuroprotective Effect of Caffeic Acid Phenethyl Ester in A Mouse Model of Alzheimer’s Disease Involves Nrf2/HO-1 Pathway[J]. Aging and disease, 2018, 9(4): 605-622.
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http://www.aginganddisease.org/EN/10.14336/AD.2017.0903     OR     http://www.aginganddisease.org/EN/Y2018/V9/I4/605
Figure 1  Experimental protocol and CAPE treatment schedule

Mice received i.p. injection of CAPE (10 mg/kg) for 10 days. Animals were sacrificed 10 or 20 days after Aβ1-42O injection.

Figure 2  Effects of CAPE (10 mg/kg) on the performance in the training and probe trials of Morris Water Maze test in Aβ<sub>1-42</sub>O-injected mice

The training trials (A) were carried out for 5 days (four per day), the probe trial was performed on day 6. Escape latency (B), time spent in the opposite quadrant to the platform zone (C) and total distance travelled from the platform zone (D) in the probe test. Values are expressed as mean ± SEM (n=10) (A: **p<0.01 vs. Sham/VH group, ***p<0.001 vs. Sham/VH group, §p<0.05 vs. AβO/VH; B: **p<0.01 vs. Sham/VH group, §p<0.05 vs. AβO/VH; C: *p<0.05 vs. Sham/VH group; D: **p<0.01 vs. Sham/VH group, §p<0.05 vs. AβO/VH; ANOVA, post hoc test Bonferroni).

Figure 3  Effects of CAPE (10 mg/kg) on the performance in Novel Object Recognition test in Aβ<sub>1-42</sub>O-injected mice

Quantitative comparison of the recognition index in the memory test session performed 24 h after the training session. Values are expressed as mean ± SEM (n=10).

Figure 4  Effects of CAPE (10 mg/kg) on neuronal cell death 10 days after Aβ<sub>1-42</sub>O injection

Representative hematoxylin and eosin staining of coronal sections containing the hippocampus. Scale bar 100 μm (A). Quantitative analysis of hematoxylin and eosin staining (B). Values are expressed as mean of fold increase ± SEM (n=10) of the density of each experimental group compared to the Sham/VH group (B: *p<0.05 vs. Sham/VH, §p<0.05 vs. AβO/VH; ANOVA, post hoc test Bonferroni).

Figure 5  Effects of CAPE (10 mg/kg) on caspase-9 activation and immunoreactivity 10 and 20 days after Aβ<sub>1-42</sub>O injection

A: Caspase-9 activation was determined using a specific chromogenic substrate in hippocampal samples. Values are expressed as mean of fold increase ± SEM (n=10) of optical density (OD) of each experimental group compared to the Sham/VH group. B: Representative photomicrographs of immunostaining for cleaved caspase-9 in brain coronal sections containing the hippocampus of AβO/VH and AβO/CAPE groups. Scale bar 100 μm. C: Quantitative analysis of the number of positive cells to caspase-9 activation. Values are expressed as mean ± SEM (n=10) of positive cells in each experimental group (A: **p<0.001 and ***p<0.001 vs. sham groups, §p<0.05 and §§p<0.01 vs. AβO/VH; C: ***p<0.001 vs. sham groups, §§§p<0.001 vs. AβO/VH; ANOVA, post hoc test Bonferroni).

Figure 6  Effects of CAPE (10 mg/kg) on cellular redox status after Aβ<sub>1-42</sub>O injection

Redox status was determined in hippocampal samples 10 and 20 days after Aβ1-42O injection (A) based on DCF’s fluorescence emission at 535 nm after excitation at 485 nm. Values are expressed as mean of fold increase ± SEM (n=10) of fluorescence intensity arbitrary units (UF) of each experimental group compared to the Sham/VH group. GSH content was measured using a colorimetric assay in hippocampal samples 10 and 20 days after Aβ1-42O injection (B). Values are calculated using a standard calibration curve and expressed as mean of fold increase ± SEM (n=10) of mmol GSH/mg protein compared to the Sham/VH group. GST and GSR mRNA relative expression (C-D) was determined in hippocampal samples 10 days after Aβ1-42O injection through the 2-ΔΔCt method. Rn 18S and ACTB were used as control housekeeping genes, calculated through the 2-ΔΔCt method and determined in hippocampal samples 10 days after Aβ1-42O injection. Values are presented as mean ± SEM of at least four different experiments (A: *p<0.05 and ***p<0.001 vs. sham groups, §p<0.05 vs. AβO/VH groups; B: *p<0.05 and ***p<0.001 vs. sham groups, §p<0.05 and §§§p<0.001 vs. AβO/VH group; C: ***p<0.001 vs. sham groups, §p<0.05 vs. AβO/VH group; d: ***p<0.001 vs. sham groups; ANOVA, post hoc test Bonferroni).

Figure 7  Effects of CAPE (10 mg/kg) on Nrf2 and HO-1 activation after Aβ<sub>1-42</sub>O injection

Nrf2 activation was detected 10 and 20 days after Aβ1-42O injection using an Nrf2-based ELISA kit on nuclear extract of hippocampal samples (A). Values are expressed as mean of fold increase ± SEM (n=10) of the optical density (OD) of each group compared to the Sham/VH group. Nrf2 mRNA relative expression (B) was determined in hippocampal samples 10 days after Aβ1-42O injection through the 2-ΔΔCt method. Rn 18S and ACTB were used as control housekeeping genes. Values are presented as mean ± SEM of at least four different experiments. HO-1 was determined 10 days after Aβ1-42O injection by Western Blotting at 28kDa and the loading control β-actin at 42kDa (C). Top: representative images of the protein expression. Bottom: quantitative analysis of the Western Blotting results for the HO-1 levels. The graphs show densitometry analysis of the bands appertaining to the protein of interest. Values are expressed as mean of fold increase ± SEM (n=10) of each group compared to the Sham/VH group (A: §§§p<0.001 vs. AβO/VH group; B: §§§p<0.001 vs. AβO/VH group; C: *p<0.05 vs. Sham/VH group, §p<0.05 vs. AβO/VH group; ANOVA, post hoc test Bonferroni).

Figure 8  Effects of CAPE (10 mg/kg) on GSK3 phosphorylation (pGSK3) after Aβ<sub>1-42</sub>O injection

pGSK3 was determined 10 and 20 days after Aβ1-42O injection by Western Blotting at 46kDa using total GSK3 as loading control (A). Top: representative images of the protein expression in hippocampus. Bottom: quantitative analysis of the Western Blotting results for the pGSK3 levels. The graphs show densitometry analysis of the bands appertaining to the protein of interest. Values are expressed as mean of fold increase ± SEM (n=10) of each group compared to the Sham/VH group. GSK3 mRNA relative expression (B) was determined in hippocampal samples 10 days after Aβ1-42O injection through the 2-ΔΔCt method. Rn 18S and ACTB were used as control housekeeping genes. Values are presented as mean ± SEM of at least four different experiments (A: **p<0.01 vs. sham groups, §p<0.05 and §§p<0.01 vs. AβO/VH group; B: §p<0.05 vs. AβO/VH group; ANOVA, post hoc test Bonferroni).

Figure 9  Effects of CAPE (10 mg/kg) on inflammatory response 10 and 20 days after Aβ<sub>1-42</sub>O injection

Representative photomicrographs (A) of immunostaining for GFAP (green) and Iba1 (red) in brain coronal sections containing hippocampal structure of AβO/VH and AβO/CAPE groups. Scale bar 100 μm. Quantitative analysis of GFAP (B) and Iba1 (C) immunostaining. Values are expressed as mean of fold increase ± SEM (n = 10) of the fluorescent intensity of each experimental group compared to the Sham/VH group (B: ***p < 0.001 vs. sham groups; §§§p<0.001 vs. AβO/VH group; C: ***p < 0.001 vs. sham groups; §p<0.05 and §§§p<0.001 vs. AβO/VH group; ANOVA, post hoc test Bonferroni).

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