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

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.

Genistein protects against Aβ25–35 induced apoptosis of PC12 cells through JNK signaling and modulation of Bcl-2 family messengers

“…In addition, results of studies in vitro and in vivo show that alterations of JNK pathways are associated with pathogenesis and apoptosis of neurons in AD [31]. Importantly, evidence shows that pretreatment with the JNK inhibitor SP600125 prior to Aβ 25–35 exposure blocked expression of Bcl-2 family members, including Bcl-w and Bim [21].…”

Mitochondrial dysfunction and cell death in neurodegenerative diseases through nitroxidative stress

“…By carefully studying the time-dependent changes in enzyme activities, mitochondrial permeability and histological features in the absence or presence of specific JNK inhibitors, it was concluded that translocation of activated p-JNK to mitochondria and subsequent phosphorylation of many mitochondrial proteins are critically important in promoting mitochondrial dysfunction, mitochondrial permeability change and necrotic tissue injury usually observed at later time points (Jang et al, 2015). Similarly, phosphorylation of many proteins such as Tau (Wang et al, 2013) and Bax in neuronal tissues can produce neurofibrillary tangles (NFTs) and apoptosis of neuronal cells, respectively, contributing to neurodegeneration (Byun et al, 2012; Byun et al, 2014; Yarza et al, 2016). However, the number and identity of the neuronal proteins, that can be phosphorylated by activated p-JNK, p-p38K, and/or GSK3β in brains (Forlenza et al, 2011; Jimenez et al, 2011; Jo et al, 2011), need to be investigated to further delineate the causal role of protein phosphorylation in promoting neurodegenerative diseases.…”

MUC1 inhibition leads to decrease in PD-L1 levels via upregulation of miRNAs

“…MUC1-silenced MOLM-14 and THP-1 cells were assessed for their expression of ERK and JNK; described mediators of c-Jun transcription 39–41 and phosphorylation, 42,43 respectively. MUC1 silencing resulted in increased levels of total and phosphorylated ERK and JNK as demonstrated by immunoblot analysis (Figures 4g and h; n = 2).…”

“…Moreover, given the marked increase in phospho c-Jun expression following MUC1 silencing, we sought to examine whether MUC1 signaling also effects c-Jun activation. Indeed, analysis of JNK expression, which has been widely shown to effect c-Jun activation, 42,43 was demonstrated to be significantly increased following MUC1 silencing in both MOLM-14 and THP-1 cells. These results are consistent with reported JNK regulation by MUC1 signaling.…”