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Graphene Oxide Ameliorates the Cognitive Impairment Through Inhibiting PI3K/Akt/mTOR Pathway to Induce Autophagy in AD Mouse Model

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Abstract

Alzheimer’s disease (AD) is a neurodegenerative disease of the central nervous system characterised by cognitive impairment. Its major pathological feature is the deposition of β-amyloid (Aβ) peptide, which triggers a series of pathological cascades. Autophagy is a main pathway to eliminate abnormal aggregated proteins, and increasing autophagy represents a plausible treatment strategy against relative overproduction of neurotoxic Aβ. Graphene oxide (GO) is an emerging carbon-based nanomaterial. As a derivative of graphene with neuroprotective effects, it can effectively increase the clearance of abnormally aggregated protein. In this article, we investigated the protective function of GO in an AD mouse model. GO (30 mg/kg, intraperitoneal) was administered for 2 weeks. The results of the Morris water maze test and the novel object recognition test suggested that GO ameliorated learning and memory impairments in 5xFAD mice. The long-term potentiation and depotentiation from the perforant path to the dentate gyrus in the hippocampus were increased with GO treatment in 5xFAD mice. Furthermore, GO upregulated the expression of synapse-related proteins and increased the cell density in the hippocampus. Our results showed that GO up-regulated LC3II/LC3I and Beclin-1 and decreased p62 protein levels in 5xFAD mice. In addition, GO downregulated the PI3K/Akt/mTOR signalling pathway to induce autophagy. These results have revealed the protective potential of GO in AD.

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Abbreviations

AD:

Alzheimer’s disease

Aβ:

β-Amyloid plaque

DEP:

Depotentiation

fEPSPs:

Field excitatory post-synaptic potentials

GO:

Graphene oxide

GQDs:

Graphene quantum dots

IT:

Initial training

LC3:

Microtubule-associated light chain 3

LFS:

Low-frequency stimulation

LTP:

Long-term potentiation

mTOR:

Mammalian target of rapamycin

MWM:

Morris water maze

NOR:

Novel object recognition

NR2B:

N-methyl-d-aspartate receptor 2B

PD:

Parkinson’s disease

PI3K:

Phosphatidylinositol-3 kinases

PSD-95:

Postsynaptic density protein 95

RET:

Reversal exploring test

RT:

Reversal training

SET:

Space exploring test

SYP:

Synaptophysin

SOD:

Superoxide dismutase

SIRTs:

Sirtuins

TEM:

Transmission electron microscopy

TBS:

Theta burst stimulation

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (Grant No. 81771979), and the Applied Basic Research Programs of Science and Technology Commission Foundation of Tianjin (18JCYBJC27400). The support from the Royal Society (UK) for International Exchanges (IEC\NSFC\181045) is thankfully acknowledged.

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Author notes

  1. Fangxuan Chu and Kai Li have the same contribution to this work.

Authors and Affiliations

  1. Medical School, State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials for Ministry of Education, College of Medicine, Nankai University, Tianjin, 300071, China

    Fangxuan Chu, Kai Li, Xiaolin Li, Lanju Xu & Zhuo Yang

  2. Department of Mechanical Engineering, University College London, London, UK

    Jie Huang

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  1. Fangxuan Chu
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Contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by FC and KL. The first draft of the manuscript was written by FC. Formal analysis and investigation: XL; Supervision, data curation and software: LX; Conceptualization, Methodology, Writing—review and editing: JH; Conceptualization, resources, writing—review and editing: ZY. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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11064_2020_3167_MOESM1_ESM.tif

Fig. S1 The expressions of SOD1 and SIRT1 in the hippocampal of four groups. (A) The immunoreactive bands of SOD1 (16 kDa), SIRT1 (110 kDa) and β-actin (43 kDa) in the hippocampal tissues. (B) Quantitative analysis of the optical density ratio of western blot densities of SOD1. (C) Quantitative analysis of the optical density ratio of western blot densities of SIRT1. The expression of proteins in western blots are normalized with β-actin. Data are presented as mean ± SEM (n = 3 per group). *p < 0.05, **p < 0.01, ***p < 0.001, compared with WT+PBS group; #p < 0.05, compared with the AD+PBS group. Supplementary file1 (TIF 605 KB)

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Chu, F., Li, K., Li, X. et al. Graphene Oxide Ameliorates the Cognitive Impairment Through Inhibiting PI3K/Akt/mTOR Pathway to Induce Autophagy in AD Mouse Model. Neurochem Res 46, 309–325 (2021). https://doi.org/10.1007/s11064-020-03167-z

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