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Review
. 2017 May 31;18(6):1168.
doi: 10.3390/ijms18061168.

Can Co-Activation of Nrf2 and Neurotrophic Signaling Pathway Slow Alzheimer's Disease?

Kelsey E Murphy  1 , Joshua J Park  2
Affiliations
Review

Can Co-Activation of Nrf2 and Neurotrophic Signaling Pathway Slow Alzheimer's Disease?

Kelsey E Murphy et al. Int J Mol Sci. .

Abstract

Alzheimer's disease (AD) is a multifaceted disease that is hard to treat by single-modal treatment. AD starts with amyloid peptides, mitochondrial dysfunction, and oxidative stress and later is accompanied with chronic endoplasmic reticulum (ER) stress and autophagy dysfunction, resulting in more complicated pathogenesis. Currently, few treatments can modify the complicated pathogenic progress of AD. Compared to the treatment with exogenous antioxidants, the activation of global antioxidant defense system via Nrf2 looks more promising in attenuating oxidative stress in AD brains. Accompanying the activation of the Nrf2-mediated antioxidant defense system that reduce the AD-causative factor, oxidative stress, it is also necessary to activate the neurotrophic signaling pathway that replaces damaged organelles and molecules with new ones. Thus, the dual actions to activate both the Nrf2 antioxidant system and neurotrophic signaling pathway are expected to provide a better strategy to modify AD pathogenesis. Here, we review the current understanding of AD pathogenesis and neuronal defense systems and discuss a possible way to co-activate the Nrf2 antioxidant system and neurotrophic signaling pathway with the hope of helping to find a better strategy to slow AD.

Keywords: Alzheimer’s disease; Nrf2; amyloid peptide; mitochondrial damage; natural products; neurotrophic signaling pathway; oxidative stress.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Multifaceted Alzheimer’s Disease (AD) pathogenesis. Aβ peptides increase calcium influx, mitochondrial permeability transition pore (mPTP) formation, tumor necrosis factor α (TNFα), and mitochondrial cytochrome c (cyt c) and reactive oxygen species (ROS) release, reduce α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor and postsynaptic density protein 95 (PSD95), and activate microglial cells that in turn induce neuroinflammation. All these negative effects lead to the gradual loss of synaptic transmission and plasticity and long-term potentiation (LTP). Aβ peptides directly attack mitochondria via its interactions with cyclophilin D (CypD) and Aβ-binding alcohol dehydrogenase (ABAD), thus causing the uncoupling of mitochondrial electron transport chain (mETC), the reduction of mitochondrial membrane potential (MMP) and adenosine tri-phosphate (ATP), and the loss of ETC enzymes including cytochrome c oxidase 4 (COX4), which result in mitochondrial dysfunction. Damaged mitochondria release ROS and reactive nitrogen species (RNS) which reduce the antioxidant enzymes and increase the peroxidation of intracellular molecules. Both chronic oxidative stress and Aβ peptides are followed by chronic endoplasmic reticulum (ER) stress. During chronic ER stress, protein kinase RNA like ER kinase (PERK) and activating transcription factor 6 (ATF6) activate C/EBP homologous protein-10 (CHOP10) that, in turn, increases pro-apoptotic proteins (growth arrest and DNA damage-inducible protein 34 [GADD34], B-cell lymphoma 2 (BCL-2) interacting mediator of cell death [BIM], p53 upregulated modulator of apoptosis [PUMA], Noxa, Bax, Bak, and ER oxidase 1α [ERO1α]) and decreases anti-apoptotic protein, Bcl-2. During chronic ER stress, inositol-requiring kinase 1α (IRE1α) activates tumor necrosis factor receptor-associated factor 2 (TRAF2)-dependent pro-apoptotic kinases, apoptosis signal-regulating kinase 1(ASK1), p38, and c-Jun N-terminal kinase (JNK) and caspase-mediated apoptosis. Chronic ER stress also contributes to oxidative stress. In AD brains, autophagy becomes dysfunctional due to the over-activation of mammalian target of rapamycin (mTOR). Inhibition of autophagy results in the accumulation of Aβ peptides and p-tau and the loss of synapses. (black arrows: cause/contribute to).
Figure 2
Figure 2
Neuronal defense systems. A group of natural products appear to activate unknown signaling pathways (dotted lines) that lead to the activation of neurotrophic (CREB) and antioxidant (Nrf2-ARE) defense systems in neurons. FGFR1 activated by fibroblast growth factors (FGFs) induces Ras-MEK and PLCγ-PKC signaling pathways that activate CREB and Nrf2. TrkB activated by brain-derived neurotrophic factor (BDNF) and 7,8-DHF induces PLCγ-PKC and PI3K-Akt signaling pathways that activate CREB and maybe Nrf2. Insulin receptors (IRs) activated by insulin or IGFs induce IRS-1-PI3K-Akt signaling pathway that activates CREB and maybe Nrf2. Activated Akt inhibits mTOR to activate autophagy, increases APP excretion and IDE expression to reduce Aβ peptides, and inhibits GSK3β to reduce p-tau. Activated CREB enhances synaptic transmission, neuron survival, and learning and memory. Activated Nrf2 binds to ARE and increases the expression of antioxidant and detoxifying enzymes involved in Fe2+ homeostasis, redox regulation, and GSH synthesis and metabolism. Activated Nrf2 also enhances mitochondrial biogenesis by increasing the expression of PGC1α, TFAM, Nrf1, and Bcl-2. (↑: increases; blue arrows: activate/cause; red lines: inhibit; light blue dotted arrows: may activate).
Figure 3
Figure 3
A better way to slow AD: Co-activation of the Nrf2-ARE antioxidant system and neurotrophic signaling pathway. In AD, Aβ peptides and oxidative stress increase ROS, attack mitochondrial integrity and overpower antioxidant system. This leads to generation of lipid peroxides, DNA, protein and organelle damage, synaptic defects, increased ER stress response, and ultimately neuron death. In order to mitigate oxidative stress in AD brains, global antioxidant defense system should be upregulated. The activation of the Nrf2-ARE antioxidant defense system has been seen via FGFs and certain flavonoids. However, unilateral activation of the antioxidant system is insufficient in altering AD progression. Activation of neurotrophic signaling pathway is also necessary for regeneration of damaged organelles, which has been evidenced in various non-flavonoid polyphenols. Synergistic co-activation of the Nrf2-ARE system and neurotrophic signaling pathway, however, may provide a greater ameliorating effect on AD pathogenesis. Co-activation of these pathways can be achieved by either a combination of the Nrf2-ARE activator and neurotrophic signaling activator or a multimodal activator such as luteolin, apigenin, 7,8-DHF, harpagoside, taurine, and R-α-lipoic acid. Either combinatory treatment or strong multimodal-effect agent will have a greater ability of ameliorating or modifying the progression of multifaceted AD by co-activating antioxidant and neurotophic signaling pathways. (↑: increase; ↓: decrease).
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