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Crosstalk between the mTOR and Nrf2/ARE signaling pathways as a target in the improvement of long-term potentiation - PubMed

Review

Crosstalk between the mTOR and Nrf2/ARE signaling pathways as a target in the improvement of long-term potentiation

Artem P Gureev et al. Exp Neurol. 2020 Jun.

Abstract

In recent years, a significant progress was made in understanding molecular mechanisms of long-term memory. Long-term memory formation requires strengthening of neuronal connections (LTP, long-term potentiation) associated with structural rearrangement of neurons. The key role in the synthesis of proteins essential for these rearrangements belong to mTOR (mammalian target of rapamycin) complexes and signaling pathways involved in mTOR regulation. Suppression of mTOR activity may impair synaptic plasticity and long-term memory, while mTOR activation inhibits autophagy, thereby potentiating amyloidosis and development of Alzheimer's disease (AD) accompanied by irreversible memory loss. Because of this, suppression/inhibition of mTOR might have unpredictable consequences on memory. The Nrf2/ARE signaling pathway affects almost all mitochondrial processes. The activation of this pathway improves memory and exhibits therapeutic effect in AD. In this review, we discuss the crosstalk between the Nrf2/ARE signaling and mTOR in the maintenance of synaptic plasticity. Nrf2 pathway can be activated by pharmacological agents and by changes in mitochondria functioning accompanying various neuronal dysfunctions.

Keywords: Alzheimer's disease; Long term memory; Neurons; Nrf2; mTOR.

Copyright © 2020 Elsevier Inc. All rights reserved.

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Figures

Figure 1.
Figure 1.. Mechanism of mTORC and Nrf2/ARE signaling crosstalk during long-term potentiation.

Membrane depolarization and glutamate binding to the postsynaptic membrane receptors induce NMDAR activation, which leads to the Ca2+ entry into the postsynaptic neuron. Ca2+ activates CaM and CaMKII, which is necessary for AMPAR phosphorylation. Upon binding to glutamate, AMPAR becomes permeable to Na+, which is necessary for strong depolarization, which is necessary for stable activation of NMDAR. Ca2+ activates MAP kinase pathways (Ras/Raf/MEK1/2-ERK1/2-Rsk), which phosphorylate CREB. CREB induces mRNA transcription for synapse growth. The activation of mTORC1 is due to BDNF, which binds to TrkB and activates PI3K. PI3K catalyzes the turnover of (PI(4,5)P2) into (PI(3,4,5)P3), which is necessary for PDK1 and Akt phosphorylation. PTEN is a negative regulator of PI3K; PI3K can directly regulate the mTORC2 complex, which regulates the actin polymerization process and cytoskeleton rearrangement. mTORC2 in turn, directly phosphorylates Akt. Akt phosphorylates and inactivates TSC1/2, which is a negative regulator of mTORC1 by downregulation of Rheb. mTORС1 activates eIF4E due to phosphorylation and inactivation of 4E-BP, which ensures translation initiation. mTORC1 activates S6K, which activates eIF4B and S6K, which are necessary for ribosomal biogenesis. ERK1/2 and Rsk can phosphorylate and inactivate TSC1/2, thereby activating mTORC1. Nrf2 translocates into nucleus and binds with ARE of mTOR promotor, and upregulates its expression, which leads to enhance of mTORC1 and mTORC2 activity. ERK1/2 can directly phosphorylate and activate Nrf2. Akt phosphorylates and inactivates GSK3β (negative regulator of Nrf2). Akt stabilizes p21, which inactivates Keap1 (negative regulator of Nrf2). ROS inactivate Keap1. NADPH oxidase is a potent ROS source that can be activated by Ca2+, which is translocated into neurons via NMDAR.

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References

    1. Abbott JJ, Howlett DR, Francis PT, Williams RJ, 2008. Abeta(1–42) modulation of Akt phosphorylation via alpha7 nAChR and NMDA receptors. Neurobiol Aging. 29, 992–1001. DOI: 10.1016/j.neurobiolaging.2007.01.003 - DOI - PubMed
    1. Aben B, Stapert S, Blokland A, 2012. About the Distinction between Working Memory and Short-Term Memory. Front Psychol. 3, 301 DOI: 10.3389/fpsyg.2012.00301. - DOI - PMC - PubMed
    1. Abramov AY, Jacobson J, Wientjes F, Hothersall J, Canevari L, Duchen MR, 2005. Expression and modulation of an NADPH oxidase in mammalian astrocytes. J Neurosci. 25, 9176–9184. DOI: 10.1523/jneurosci.1632-05.2005 - DOI - PMC - PubMed
    1. Angliker N, Rüegg MA, 2013. In vivo evidence for mTORC2-mediated actin cytoskeleton rearrangement in neurons. Bioarchitecture. 3, 113–118. DOI: 10.4161/bioa.26497. - DOI - PMC - PubMed
    1. Atri A, 2019. Current and Future Treatments in Alzheimer’s Disease. Semin Neurol. 39, 227–240. DOI: 10.1055/s-0039-1678581. - DOI - PubMed

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