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. 2019 Jan 26;11(2):536-548.
doi: 10.18632/aging.101759.

Geniposide-mediated protection against amyloid deposition and behavioral impairment correlates with downregulation of mTOR signaling and enhanced autophagy in a mouse model of Alzheimer's disease

Zhihua Zhang  1   2 , Xiaojian Wang  1   3 , Di Zhang  4 , Yueze Liu  5 , Lin Li  1
Affiliations

Geniposide-mediated protection against amyloid deposition and behavioral impairment correlates with downregulation of mTOR signaling and enhanced autophagy in a mouse model of Alzheimer's disease

Zhihua Zhang et al. Aging (Albany NY). .

Abstract

Geniposide, an iridoid glycoside extract from the gardenia fruit, is used in traditional Chinese medicine to alleviate symptoms of liver and inflammatory diseases. Geniposide activates GLP-1 receptors, known to modulate the activity of mechanistic target of rapamycin (mTOR), a key kinase regulating energy balance, proliferation, and survival in cells. mTOR activation inhibits autophagy, which is often disrupted in age-related diseases. Modulation of mTOR function to increase autophagy and inhibit apoptosis is involved in the protective effects of pharmacologic agents targeting diabetes and Alzheimer's disease (AD). We investigated whether such mechanism could mediate geniposide's neuroprotective effects in the APP/PS1 mouse model of AD. Eight-week treatment with geniposide improved cognitive scores in behavioral tests, reduced amyloid-β 1-40 plaque deposition, and reduced soluble Aβ1-40 and Aβ1-42 levels in the APP/PS1 mouse brain.This also showed increased p-Akt/Akt, p-mTOR/mTOR and decreased p-4E-BP1/4E-BP1 expression, and these patterns were partially reversed by geniposide. Evidence for enhanced autophagy, denoted by increased expression of LC3-II and Beclin1, was also seen after treatment with geniposide. Our data suggests that down regulation of mTOR signaling, leading to enhanced autophagy and lysosomal clearance of Aβ fibrils, underlies the beneficial effects of geniposide against neuropathological damage and cognitive deficits characteristic of AD.

Keywords: APP/PS1 mice; Alzheimer’s disease; autophagy; geniposide; mechanistic target of rapamycin.

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Conflict of interest statement

CONFLICTS OF INTEREST: The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Overview of the experimental design. APP/PS1 and WT mice were treated with geniposide (50 mg/kg/d) or water, respectively, via intragastric administration every day for 8 weeks. The NOR test was conducted in the sixth week, and the MWM test was conducted in the seventh week. On week eight mice were killed for biochemical analyses.
Figure 2
Figure 2
Geniposide improves NOR scores in APP/PS1 mice. (A) Schematic diagram of the NOR test. (B) NOR test results. The DI of APP/PS1 mice was significantly decreased compared to WT, and was improved by geniposide treatment. Data are mean ± SEM (n = 13–15). ***p < 0.001 vs. WT; #p < 0.05 vs. APP/PS1. (one-way ANOVA, Tukey's Multiple Comparison Test). WT: wild-type mice. GP: geniposide.
Figure 3
Figure 3
Geniposide improves learning and memory in APP/PS1 mice. (A) Escape latency in the MWM’s place navigation test was significantly longer in APP/PS1 mice compared to WT on days 3–5, and shortened by day 5 in mice treated with geniposide. (B) Path length (swimming distance) was longer in APP/PS1 mice than in WT mice on days 3–5, and shortened by day 5 in geniposide-treated mice. (C) The number of crossings over the area where the escape platform was previously located (spatial probe test) was decreased in APP/PS1 mice compared to WT. This decrease was partly reversed after geniposide treatment. (D) The time spent in the target quadrant was decreased in APP/PS1 mice compared to WT, and this was partly improved by geniposide. (E) Swimming speed did not differ between groups. (F) Swimming time to arrive at visible platform did not differ between groups. (G) Swimming tracks. Data are presented as mean ± SEM (n = 13–15). ***p < 0.001 vs. WT; #p < 0.05 vs. geniposide-treated APP/PS1 mice (two-way ANOVA, Tukey's Multiple Comparison Test). WT: wild-type mice. GP: geniposide.
Figure 4
Figure 4
Geniposide ameliorates neuropathological changes in APP/PS1 mice. Sections obtained from the hippocampus (A) and cortex (B) were stained with HE. Neurons in WT mice were normal in shape and orderly arranged. In APP/PS1 mice, neurons were lost and darkly stained. Shrinkage and necrosis were observed in scattered neurons (yellow arrow). Geniposide treatment reduced these pathological changes. A) A-C, 4× magnification; D-F, 20× magnification; B) A-C, 2× magnification; D-F, 40× magnification).
Figure 5
Figure 5
Geniposide attenuates Aβ1-40 plaque formation in the hippocampi of APP/PS1 mice. (A) Representative images of Aβ1-40-stained brain sections (A-C: 4× magnification; D-F: 10× magnification). (B) Percentage of the area occupied by Aβ 1-40 plaques. (C) Quantification of Aβ plaque density. Data are presented as mean ± SEM (n = 6). ##p < 0.01, ###p < 0.001 (one-way ANOVA, Tukey's Multiple Comparison Test). WT: wild-type mice. GP: geniposide.
Figure 6
Figure 6
Geniposide reduces soluble Aβ1-40 and Aβ1-42 levels in hippocampi of APP/PS1 mice. Soluble Aβ1-40 (A) and Aβ1-42 (B) levels were measured by ELISA in the hippocampi of WT and APP/PS1 mice. In the latter, geniposide treatment lowered the expression of both Aβ alloforms. Data are presented as mean ± SEM (n = 6). #p < 0.05 (one-way ANOVA, Tukey's Multiple Comparison Test). WT: wild-type mice. GP: geniposide.
Figure 7
Figure 7
Geniposide upregulates the expression of autophagy markers in the hippocampi of APP/PS1 mice. (A) Representative images of LC3-II-stained brain sections and quantification of LC3-II-positive neurons; (B) Representative images of Beclin1-stained brain sections and quantification of Beclin1-positive neurons. Numbers of both LC3-II and Beclin1 positive neurons in APP/PS1 mice were reduced compared to WT, and geniposide reversed those reductions. (A-C, 4× magnification; D-F, 40× magnification). Data are presented as mean ± SEM (n = 6). *** p < 0.001, APP/PS1 mice vs. WT; ### p < 0.001, geniposide-treated vs. untreated APP/PS1 mice (one-way ANOVA, Tukey's Multiple Comparison Test). WT: wild-type mice. GP: geniposide.
Figure 8
Figure 8
Geniposide treatment decreases mTOR activation markers in brains of APP/PS1 mice. Hippocampal expression of Akt, mTOR, and 4E-BP1, and their respective phosphorylated forms was detected by western blot. The expression of p-Akt (A) and p-mTOR (B) was enhanced in APP/PS1 mice compared to WT, and geniposide attenuated this increase. The expression of p-4E-BP1 (C) in APP/PS1 mice was reduced compared to WT, and geniposide partly restored this decrease. Data are presented as mean ± SEM (n = 6). ***p < 0.001, **p < 0.01, *p < 0.05 vs. WT; #p < 0.05 vs. APP/PS1 mice (one-way ANOVA, Tukey's Multiple Comparison Test). WT: wild-type mice. GP: geniposide.
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References

    1. Johnson SC, Rabinovitch PS, Kaeberlein M. mTOR is a key modulator of ageing and age-related disease. Nature. 2013;493:338–45. doi: 10.1038/nature11861. - DOI - PMC - PubMed
    1. Caccamo A, Maldonado MA, Majumder S, Medina DX, Holbein W, Magrí A, Oddo S. Naturally secreted amyloid-beta increases mammalian target of rapamycin (mTOR) activity via a PRAS40-mediated mechanism. J Biol Chem. 2011;286:8924–8932. doi: 10.1074/jbc.M110.180638. - DOI - PMC - PubMed
    1. Spilman P, Podlutskaya N, Hart MJ, Debnath J, Gorostiza O, Bredesen D, Richardson A, Strong R, Galvan V. Inhibition of mTOR by rapamycin abolishes cognitive deficits and reduces amyloid-beta levels in a mouse model of Alzheimer’s disease. PLoS One. 2010;4:e9979. doi: 10.1371/journal.pone.0009979. - DOI - PMC - PubMed
    1. Zhang S, Salemi J, Hou H, Zhu Y, Mori T, Giunta B, Obregon D, Tan J. Rapamycin promotes beta-amyloid production via ADAM-10 inhibition. Biochem Biophys Res Commun. 2010;398:337–341. doi: 10.1016/j.bbrc.2010.06.017. - DOI - PMC - PubMed
    1. Benedict C, Grillo CA. Insulin Resistance as a Therapeutic Target in the Treatment of Alzheimer's Disease: A State-of-the-Art Review. Front Neurosci. 2018;12:215. doi: 10.3389/fnins.2018.00215. - DOI - PMC - PubMed

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