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Review
. 2016 Jan 12:6:321.
doi: 10.3389/fphar.2015.00321. eCollection 2015.

c-Jun N-terminal Kinase (JNK) Signaling as a Therapeutic Target for Alzheimer's Disease

Ramon Yarza  1 , Silvia Vela  1 , Maite Solas  2 , Maria J Ramirez  2
Affiliations
Review

c-Jun N-terminal Kinase (JNK) Signaling as a Therapeutic Target for Alzheimer's Disease

Ramon Yarza et al. Front Pharmacol. .

Abstract

c-Jun N-terminal kinases (JNKs) are a family of protein kinases that play a central role in stress signaling pathways implicated in gene expression, neuronal plasticity, regeneration, cell death, and regulation of cellular senescence. It has been shown that there is a JNK pathway activation after exposure to different stressing factors, including cytokines, growth factors, oxidative stress, unfolded protein response signals or Aβ peptides. Altogether, JNKs have become a focus of screening strategies searching for new therapeutic approaches to diabetes, cancer or liver diseases. In addition, activation of JNK has been identified as a key element responsible for the regulation of apoptosis signals and therefore, it is critical for pathological cell death associated with neurodegenerative diseases and, among them, with Alzheimer's disease (AD). In addition, in vitro and in vivo studies have reported alterations of JNK pathways potentially associated with pathogenesis and neuronal death in AD. JNK's, particularly JNK3, not only enhance Aβ production, moreover it plays a key role in the maturation and development of neurofibrillary tangles. This review aims to explain the rationale behind testing therapies based on inhibition of JNK signaling for AD in terms of current knowledge about the pathophysiology of the disease. Keeping in mind that JNK3 is specifically expressed in the brain and activated by stress-stimuli, it is possible to hypothesize that inhibition of JNK3 might be considered as a potential target for treating neurodegenerative mechanisms associated with AD.

Keywords: D-JNKI1; SP600125; apoptosis; inhibitors; kinase; tau; βamyloid.

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Figures

FIGURE 1
FIGURE 1
Simplified diagram showing mechanisms involved in activation of the JNK pathway. Different stress conditions might activate JNK signaling via scaffold proteins. UPR and an interaction between Ire1 and PS1 have also been described as potential activators of JNK. ROS, radical oxygen species; Aβ, βamyloid; JIP, JNK interacting protein; UPR, unfolded protein response; Ire, endoplasmic reticulum to nucleus signaling 1.
FIGURE 2
FIGURE 2
Cellular mechanisms activated by JNK phosphorylation. Activated JNK leads to phosphorylation of c-Jun, which modulates gene expression as well as tangle maturation. JNK plays also a direct role in the formation of tangles by phosphorylation of Tau and it also contributes to the regulation of PHF formation and proteolytic cleavage processing. Finally, JNK is responsible for the phosphorylation of BIM and BMF and, as consequence, for the activation of caspases leading to cellular apoptosis.
FIGURE 3
FIGURE 3
Pharmacology of JNK inhibitors, targets and mechanism of action. CPPi, cell-permeable peptide inhibitors; ATP-c, direct ATP-competitive inhibitors; MLKi, mixed linage kinase inhibitors.
See this image and copyright information in PMC

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