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. 2024 May 11;14(5):488.
doi: 10.3390/brainsci14050488.

Intranasal Administration of Apelin-13 Ameliorates Cognitive Deficit in Streptozotocin-Induced Alzheimer's Disease Model via Enhancement of Nrf2-HO1 Pathways

Hai Lu  1   2 , Ming Chen  1 , Cuiqing Zhu  1
Affiliations

Intranasal Administration of Apelin-13 Ameliorates Cognitive Deficit in Streptozotocin-Induced Alzheimer's Disease Model via Enhancement of Nrf2-HO1 Pathways

Hai Lu et al. Brain Sci. .

Abstract

Background: The discovery of novel diagnostic methods and therapies for Alzheimer's disease (AD) faces significant challenges. Previous research has shed light on the neuroprotective properties of Apelin-13 in neurodegenerative disorders. However, elucidating the mechanism underlying its efficacy in combating AD-related nerve injury is imperative. In this study, we aimed to investigate Apelin-13's mechanism of action in an in vivo model of AD induced by streptozocin (STZ).

Methods: We utilized an STZ-induced nerve injury model of AD in mice to investigate the effects of Apelin-13 administration. Apelin-13 was administered intranasally, and cognitive impairment was assessed using standardized behavioral tests, primarily, behavioral assessment, histological analysis, and biochemical assays, in order to evaluate synaptic plasticity and oxidative stress signaling pathways.

Results: Our findings indicate that intranasal administration of Apelin-13 ameliorated cognitive impairment in the STZ-induced AD model. Furthermore, we observed that this effect was potentially mediated by the enhancement of synaptic plasticity and the attenuation of oxidative stress signaling pathways.

Conclusions: The results of this study suggest that intranasal administration of Apelin-13 holds promise as a therapeutic strategy for preventing neurodegenerative diseases such as AD. By improving synaptic plasticity and mitigating oxidative stress, Apelin-13 may offer a novel approach to neuroprotection in AD and related conditions.

Keywords: Alzheimer’s disease; Nrf2-HO-1 signaling pathway; apelin-13; intranasal administration; oxidative stress.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Effect of intranasal administration of Apelin-13 on cognitive impairment in STZ-induced animal model of AD mice. (A) Experimental timeline. (B) Distance of mouse movement during the 15 min test period for different groups (one-way ANOVA, p > 0.05). (C) Movement time during the 15 min test period for different groups (one-way ANOVA, p > 0.05). (D) Percentage of time spent in the margin area for different groups (one-way ANOVA, p > 0.05). (E) The swimming trajectory of mice during the probe test, Blue and red dots represent the starting and ending points of the mouse trajectories, respectively. Blue circles indicate the location of the platform. (F) Average speed of different groups (one-way ANOVA, p > 0.05). (G) Quadrant time of different groups (one-way ANOVA, * p < 0.05 compared to the control group, # p < 0.05 compared to the STZ treatment group). (H) Target quadrant entry times of different groups (one-way ANOVA, * p < 0.05 compared to the control group, # p < 0.05 compared to the STZ treatment group). (I) Y-maze test. (J) Number of arm entrances of different groups (one-way ANOVA, p > 0.05). (K) Alternation ratio of different groups (one-way ANOVA, * p < 0.05 compared to control group, # p < 0.05 compared to STZ treatment group). Data are shown as the mean ± s.e.m.
Figure 2
Figure 2
Effect of intranasal administration of Apelin-13 on LTP in CA1 neurons of STZ-induced AD mice. (A) Typical traces in different treatment groups. (B) Bar graphs showing changes in LTP for different treatment groups (n = 6, one-way ANOVA, * p < 0.05 compared to control, # p < 0.05 compared to STZ treatment group). (C) Left: Typical recording cell images (upper panel: bar = 200 μm, lower panel: bar = 50 μm). Right: Time course of the LTP in different treatment groups (n = 6). Data are shown as the mean ± s.e.m.
Figure 3
Figure 3
Effect of intranasal administration of Apelin-13 on STZ-induced oxidative stress in the hippocampus. (A) Specific activity (U/mg) of SOD in each treatment group (n = 3, one-way ANOVA, * p < 0.05 compared to control, # p < 0.05 compared to STZ treatment group). (B) Specific activity (U/mg) of CAT in each treatment group (n = 3, one-way ANOVA, * p < 0.05 compared to control, # p < 0.05 compared to STZ treatment group). (C) Specific activity (U/mg) of GSH in each treatment group (n = 3, one-way ANOVA, * p < 0.05 compared to control, # p < 0.05 compared to STZ treatment group). (D) The level (nmol/mg) of MDA in each treatment group (n = 3, one-way ANOVA, * p < 0.05 compared to control, # p < 0.05 compared to STZ treatment group). Data are shown as the mean ± s.e.m.
Figure 4
Figure 4
Effect of intranasal administration of Apelin-13 on the expression of ERK-Nrf2-HO-1 in STZ-induced AD mice. (A) Representative image of immunoblots and densitometric analysis of changes in levels of ERK family proteins in different treatment groups (n = 3, one-way ANOVA, * p < 0.05 compared to control). (B) Representative image of immunoblots and densitometric analysis of changes in levels of Nrf2 proteins in different treatment groups (n = 3, one-way ANOVA, * p < 0.05 compared to control, # p < 0.05 compared to STZ treatment group). (C) Representative image of immunoblots and densitometric analysis of changes in levels of HO-1 proteins in different treatment groups (n = 3, one-way ANOVA, * p < 0.05 compared to control, # p < 0.05 compared to STZ treatment group). Data are shown as the mean ± s.e.m.
Figure 5
Figure 5
Effect of Nrf2-HO-1 pathway blockade on Apelin-13-mediated improvement of Morris maze performance in STZ-induced AD mice. (A) Experimental timeline. (B) Average speed of different groups (one-way ANOVA, p > 0.05). (C) Quadrant time of different groups (n = 8, one-way ANOVA, * p < 0.05 compared to the control group, # p < 0.05 compared to STZ treatment group, & p < 0.05 compared to STZ+Apelin-13 treatment group). (D) Target quadrant entry times in different groups (n = 8, one-way ANOVA, * p < 0.05 compared to the control group, # p < 0.05 compared to STZ treatment group, & p < 0.05 compared to STZ+Apelin-13 treatment group). Data are shown as the mean ± s.e.m.
Figure 6
Figure 6
Effect of Nrf2-HO-1 pathway blockade on Apelin-13-mediated improvement of Y-maze performance in STZ-induced animal model of AD mice. (A) Experimental timeline. (B) Number of arm entrances of different groups (one-way ANOVA, p > 0.05). (C) Alternation ratio of different groups (n = 8, one-way ANOVA, * p < 0.05 compared to the control group, # p < 0.05 compared to STZ treatment group, & p < 0.05 compared to STZ+Apelin-13 treatment group). Data are shown as the mean ± s.e.m.
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