c-Jun N-Terminal Kinase Inhibitors as Potential Leads for New Therapeutics for Alzheimer’s Diseases

Abstract

Alzheimer’s Disease (AD) is becoming more prevalent as the population lives longer. For individuals over 60 years of age, the prevalence of AD is estimated at 40.19% across the world. Regarding the cognitive decline caused by the disease, mitogen-activated protein kinases (MAPK) pathways such as the c-Jun N-terminal kinase (JNK) pathway are involved in the progressive loss of neurons and synapses, brain atrophy, and augmentation of the brain ventricles, being activated by synaptic dysfunction, oxidative stress, and excitotoxicity. Nowadays, AD symptoms are manageable, but the disease itself remains incurable, thus the inhibition of JNK3 has been explored as a possible therapeutic target, considering that JNK is best known for its involvement in propagating pro-apoptotic signals. This review aims to present biological aspects of JNK, focusing on JNK3 and how it relates to AD. It was also explored the recent development of inhibitors that could be used in AD treatment since several drugs/compounds in phase III clinical trials failed. General aspects of the MAPK family, therapeutic targets, and experimental treatment in models are described and discussed throughout this review.

JNK Pathway in CNS Pathologies

“…AD is the most frequent neurodegenerative disorder, and is based on the aggregation of neurofibrillary tangles and Aβ peptide deposition in cortical and hippocampal neurons (reviewed in [ 55 ]). Aβ–JNK mechanisms attenuate the expression of antiapoptotic Bcl-2 genes, required for the apoptosis of cortical neurons that occur in AD progression [ 56 ].…”

“…JNK3 phosphorylated levels correlate with the progression of AD [ 58 , 59 ]. In vitro and in vivo models of AD have demonstrated that JNK knockout reduces synapse loss, Aβ depositions and neuronal cell death [ 54 , 55 , 60 ]. All together, these results indicate that JNK signalling plays a central role in AD neurodegeneration, but JNK also has emerged as a potential biomarker for early diagnosis, and a potential target to prevent neuronal cell death [ 55 ].…”

“…In vitro and in vivo models of AD have demonstrated that JNK knockout reduces synapse loss, Aβ depositions and neuronal cell death [ 54 , 55 , 60 ]. All together, these results indicate that JNK signalling plays a central role in AD neurodegeneration, but JNK also has emerged as a potential biomarker for early diagnosis, and a potential target to prevent neuronal cell death [ 55 ]. The first synthesized therapeutic candidate was the SP600125 JNK inhibitor, which prevents neuronal cell death in vitro and in vivo in AD models [ 55 ].…”

“…All together, these results indicate that JNK signalling plays a central role in AD neurodegeneration, but JNK also has emerged as a potential biomarker for early diagnosis, and a potential target to prevent neuronal cell death [ 55 ]. The first synthesized therapeutic candidate was the SP600125 JNK inhibitor, which prevents neuronal cell death in vitro and in vivo in AD models [ 55 ]. However, several studies reported that this ATP-competitive inhibitor is not selective for JNK isoforms, and binds to other JNK nonrelated kinases [ 61 ].…”

“…Thus, the lack of specificity and the variety of toxicity degrees that it provokes require further research. Based on that, multiple new JNK inhibitors have been designed within recent years to target AD models [ 55 , 62 ]. However, specificity and toxicity of JNK inhibitors require further studies.…”