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Neuronostatin Promotion Soluble Aβ1-42 Oligomers: Induced Dysfunctional Brain Glucose Metabolism in Mice

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Abstract

Neuronostatin (NST) is an endogenous peptide hormone, it has the ability to improve oligomeric Aβ (oAβ)-induced cognitive impairments and increase blood glucose levels in mice. However, the relationship between NST and oAβ regarding brain glucose metabolism has not yet been established. The present study defined the contributions of NST and oAβ in the brain glucose metabolism in mice. It was found that i.c.v. co-administration of NST (3 nmol/mouse) and oAβ (1 nmol/mouse) decreased the mRNA expressions of glucose-6-phosphate dehydrogenase and phosphofructokinase. The treatments were observed to reduce ATP production and the enzyme activities of glucose-6-phosphate dehydrogenase and hexokinase in both the cortex and hippocampus. Simultaneously, co-injection of NST and oAβ inhibited the mRNA and protein expression of glucose transporters GLUT3 and GLUT1 in the cortex and hippocampus. NST promoted the oAβ-induced decreased the cortical NeuN staining, while oAβ increased the levels of NST in both the cortex and hippocampus. I.c.v. co-administration of NST and oAβ led to increase the levels of GPR107 expression and the phosphorylation of PKA, Akt, PERK and eIF-2α in the cortex. These findings suggest that NST promoted oAβ-induced dysfunctional glucose metabolism through the GPR107/PKA/Akt signaling pathway and PERK/eIF2α axis in the brain, which thus contributes to metabolic dysfunction and Alzheimer’s disease (AD) pathophysiology.

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Fig. 1
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(a) and hippocampus (b), which were measured using western blot for the immunoblots of GLUT1 and GLUT3, the immunoreactivity of GLUT1 was normalized to β-actin, and GLUT3 to GAPDH. The data are represented as the mean ± SEM from four individual mice in each group. *Indicates P < 0.05 and **Indicates P < 0.01, which are compared to the controls by the Tukey’s test; #Indicates P < 0.05 between oAβ and NST + oAβ by Student’s t test

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Abbreviations

AD:

Alzheimer’s disease

oAβ:

Aβ42 oligomers

ECL:

Chemiluminescence

eIF2α:

Eukaryotic initiation factor 2α

FDG:

Fluorodeoxyglucose

GSK3β:

Glucogen synthase kinase 3

G6PD:

Glucose-6-phosphate dehydrogenase

GLUT:

Glucose transporter

GAPDH:

Glyceraldehyde 3-phosphate dehydrogenase

GPR107:

G-protein-coupled receptor 107

HK:

Hexokinase

I.c.v.:

Intracerebroventricular

NST:

Neuronostatin

PPP:

Pentose phosphate pathway

PFK:

Phosphofructokinase

PET:

Positron emission tomography

PKA:

Protein kinase A

Akt:

Protein kinase B

PERK:

PKR-like ER kinase

RT-qPCR:

Quantitative real-time PCR

ROS:

Reactive oxygen species

SST:

Somatostatin

TBP:

TATA binding protein

TCA:

Tricarboxylic acid

UPR:

Unfolded protein response

HFIP:

1,1,1,3,3,3-Hexafluoro-2-propanol

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Acknowledgements

This work was funded by Natural Science Foundation of Gansu Province (Grant No.18JR3RA101); Youth Science and Technology Talents Lifting Project Foundation of Gansu Province, and Doctoral Launching Foundation of Northwest Normal University.

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Authors and Affiliations

  1. College of Life Sciences, Northwest Normal University, Lanzhou, Gansu, 730070, China

    Shaobin Yang, Feng Zhou, Mei Ma, Yaqin Yuan, Shengyou Zhao & Peng Yu

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  1. Shaobin Yang
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Contributions

The conception and design of the work were prepared by YS and YP. The experiment was performed by YS, ZF, YY, MM, and ZS, while the analysis and interpretation of data were done by YS and YP. Drafting of the manuscript was done by YS and YP.

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Correspondence to Peng Yu.

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All experiments were conducted in compliance with the ARRIVE guidelines.

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Yang, S., Zhou, F., Ma, M. et al. Neuronostatin Promotion Soluble Aβ1-42 Oligomers: Induced Dysfunctional Brain Glucose Metabolism in Mice. Neurochem Res 45, 2474–2486 (2020). https://doi.org/10.1007/s11064-020-03106-y

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