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. 2016 Jun 27;23(1):49.
doi: 10.1186/s12929-016-0266-z.

Erinacine A-enriched Hericium Erinaceus Mycelium Ameliorates Alzheimer's Disease-Related Pathologies in APPswe/PS1dE9 Transgenic Mice

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Free PMC article

Erinacine A-enriched Hericium Erinaceus Mycelium Ameliorates Alzheimer's Disease-Related Pathologies in APPswe/PS1dE9 Transgenic Mice

Tzeng Tsai-Teng et al. J Biomed Sci. .
Free PMC article

Abstract

Background: The fruiting body of Hericium erinaceus has been demonstrated to possess anti-dementia activity in mouse model of Alzheimer's disease and people with mild cognitive impairment. However, the therapeutic potential of Hericium erinaceus mycelia on Alzheimer's disease remains unclear. In this study, the effects of erinacine A-enriched Hericium erinaceus mycelia (HE-My) on the pathological changes in APPswe/PS1dE9 transgenic mouse model of Alzheimer's disease are studied.

Results: After a 30 day oral administration to 5 month-old female APPswe/PS1dE9 transgenic mice, we found that HE-My and its ethanol extracts (HE-Et) attenuated cerebral Aβ plaque burden. It's worth noting that the attenuated portion of a plaque is the non-compact structure. The level of insulin-degrading enzyme was elevated by both HE-My and HE-Et in cerebral cortex. On the other hand, the number of plaque-activated microglia and astrocytes in cerebral cortex and hippocampus were diminished, the ratio of nerve growth factor (NGF) to NGF precursor (proNGF) was increased and hippocampal neurogenesis was promoted after these administrations. All the mentioned benefits of these administrations may therefore improve the declined activity of daily living skill in APPswe/PS1dE9 transgenic mice.

Conclusions: These results highlight the therapeutic potential of HE-My and HE-Et on Alzheimer's disease. Therefore, the effective components of HE-My and HE-Et are worth to be developed to become a therapeutic drug for Alzheimer's disease.

Keywords: APPswe/PS1dE9 transgenic mice; Alzheimer’s disease; Amyloid β; Erinacine A-enriched Hericium erinaceus mycelia; Insulin-degrading enzyme; Neurogenesis.

Figures

Fig. 1
Fig. 1
The representative chemical finger prints and the structure of the major components of Hericium erinaceus mycelium. a. UPLC chromatogram of HE-Et was carried out on a Thermo syncronis C18 (2.1 × 100 mm) column in Waters AcQuity Ultra Performance LC system with a diode array detector, monitored at 210 nm. The mobile phase consisted of 0.1 % phosphate water (a) and acetonitrile (b) using a gradient elution of 20–55 % B at 0–2 min, 55–90 % B at 2–9 min, 90–100 % acetonitrile at 9–10 min. The flow rate was 0.4 ml/min. Three active components: HE-A, HE-C and HE-S were identified and compared to the standards, and their structure was shown in b
Fig. 2
Fig. 2
HE-Et and HE-My reduce amyloid plaque burden in the area include the cerebral cortex and hippocampus of APP/PS1 mice. Five month-old APP/PS1 mice were orally administered with vehicle (Veh, n = 6), HE-Et (n = 5) and HE-My (n = 6) for 30 days. A. The representative fluorescent images of amyloid plaques detected by thioflavin S (ThS) staining (white in a, e and i, and green in c, d, g, h, k and l) and immunohistochemical staining with AB-10 antibody (white in b, f and j, red in c, d, g, h, k and l) in the area including parietal cortex and hippocampus. Sale bar: 500 μm. A typical plaque is magnified and shows in the right side of each image. Sale bar: 20 μm. B. shows both the plaque number and burden in ThS- and AB-10-stained semi-cerebral sphere calculated by image analysis software. Plaque burden is displayed as a percentage of the area occupied by ThS- or AB-10-stained signal in the full area of interest. C. The structure of amyloid plaque in the cerebral cortex of APP/PS1 mice. The amyloid plaque in cerebral cortex of 6 months-old APP/PS1 mice was detected by ThS-staining (white in a and d, and green in c and f) and immunohistochemical staining with AB-10 antibody (white in b and e, and red in c and f). Upper panels show the representative Z-projection (3 dimensions, XYZ, A-C) of a typical plaque. Lower panels show the 2 dimensional images (XY, XZ, and YZ, D-F). The image indicated by arrow indicated the putative plaque unit. Sale bar: 10 μm. Single fluorescent images were presented as grayscale to enhance resolution
Fig 3
Fig 3
HE-Et reduces size of AB-10-stained plaque in the area including cerebral cortex and hippocampus of APP/PS1 mice. a. The representative images of ThS (green)- and AB-10 (red)-stained plaques (60 for each) selected in order of decreasing size from the area include the cerebral cortex and hippocampus of vehicle- and HE-Et-treated APP/PS1 mice. b. A scatter plot of ThS- and AB-10-stained areas from representative samples with vehicle and HE-Et treatments (solid lines: linear regression lines; dashed lines: 95 % confidence intervals; R 2 = 0.8224 for vehicle and R 2 = 0.9079 for HE-Et). c. The levels of soluble and insoluble Aβ1-42 determined by ELISA. The results are the mean ± S.D. Significant differences between treated and control (Veh) groups are indicated by *, p < 0.05
Fig. 4
Fig. 4
HE-Et and HE-My alleviate amyloid plaque-associated glial activation in the area including hippocampal and cortex of APP/PS1 mice. Five month-old APP/PS1 mice were orally administered with vehicle (Veh, n = 6), HE-Et (n = 5) and HE-My (n = 6) for 30 days. Amyloid plaques were detected by immunohistochemical staining with AB-10 antibody (blue). Microglia and reactive astrocytes were detected by immunohistochemical staining with Iba-1 antibody (red) and GFAP antibody (green), respectively. a. The representative immunostaining images of hippocampus and partial cortex. Sale bar: 500 μm. b. The enlarged views of a typical cluster which is indicated in panel a (arrow). Sale bar: 50 μm. c. Both the number of microglial and astroglial cluster in semi-cerebral sphere calculated by image analysis software. d. The immunoblotting of Iba-1 and GFAP. Representative immunoblots of the Iba-1, GFAP and β-actin were showed (left panel). The relative levels of Iba-1 and GFAP were expressed as percentage of control (Veh) (right panel). The results are the mean ± S.D. Significant differences between treated and control (Veh) groups are indicated by *, p < 0.05; **, p < 0.01; ***, p < 0.001
Fig 5
Fig 5
Effects of HE-Et and HE-My on the level of the proteins regulating Aβ accumulation and the level of NGF in cerebral cortex of APP/PS1 mice. Five months-old APP/PS1 mice were orally administered with vehicle (Veh, n = 6), HE-Et (n = 5) and HE-My (n = 5) for 30 days. Cortex was removed and homogenized, and the proteins involving in amyloidogenesis and amyloid clearance and NGF maturation in lysates were analyzed by immunoblotting. a The representative immunoblots of APP, CTF-α, −β, IDE, neprilysin and β-actin (left panel). The level of APP, CTF-α and -β, IDE and neprilysin was presented as percentage of control (Veh) (right panel). b The representative immunoblots of the proNGF, NGF and β-actin (left panel). The relative level of NGF/proNGF ratio was presented as percentage of control (Veh) (right panel). The results are the mean ± S.D. Significant differences between treated and control (Veh) groups are indicated by *, p < 0.05; **, p < 0.01
Fig. 6
Fig. 6
HE-My and HE-Et promotes hippocampal neurogenesis in APP/PS1 mice. Five months old wild type (WT) or APP/PS1 mice were orally administered with vehicle (Veh, n = 6), HE-Et (n = 6) and HE-My (n = 6) for 30 days. Hippocampal neurogenesis was detected by immunohistochemical staining with doublecortin (DCX) antibody (red) and BrdU antibody (green). a. The representative immunostaining images of dentate gyrus in wild type (WT, n =7) mice and APP/PS1 mice treated with vehicle (Veh), HE-Et and HE-My. Arrow indicates DCX-labeled newly born neuron; arrow head indicates proliferating type 2 neuroprogenitor; double arrow head indicates the newly born neuron immediately after proliferation; hollow arrow indicates proliferating cells other than neuroprogenitor. Scale bar: 100 μm. ML, molecular layer; UGL, upper blade granular cell layer; LGL, SGZ, subgranular zone; lower blade granular cell layer. b. The number of BrdU positive cells, doublecortin positive cells and the cells with double labeling (cell number/mm SGZ). The results are the mean ± SD. Significant differences between wild type (WT) and APP/PS1 groups are indicated by *, p < 0.05. Significant differences between treated and control (Veh) groups are indicated by #, p < 0.05; ##, p < 0.01
Fig. 7
Fig. 7
The deficit on nest construction displayed by APP/PS1 mice were improved by HE-My treatment. Five months old wild type (WT) or APP/PS1 mice were orally administered with vehicle (Veh, n = 6) or HE-My (n = 6) for 81 days and then nest construction test were performed. The representative images of the nest construction (a), the nest score (b) and unshredded nestlet (c) were shown. The results are the mean ± SD. Significant differences between WT (n = 8) and APP/PS1 groups are indicated by **, p < 0.01; ***, p < 0.001. Significant differences between treated and control (Veh) groups are indicated by #, p < 0.05

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