Inhibition of Phosphorylation of JNK Suppresses Aβ-Induced ER Stress and Upregulates Prosurvival Mitochondrial Proteins in Rat Hippocampus.
ABSTRACT A growing body of evidence indicates that c-Jun N-terminal kinases (JNKs) is activated in Alzheimer's disease. Herein, we examine the effect of the JNK specific inhibitor, SP600125, on the level of functional proteins or transcription factors related to endoplasmic reticulum (ER) and oxidative stress induced by amyloid beta (Aβ). Our results clearly showed the ability of SP600125 to decrease the levels of caspase 12 and calpain 2, two important enzymes involved in ER stress. Aβ has been suggested to be able to decrease the phosphorylation level of cAMP response element-binding (CREB) through mitogen-activated protein kinase pathway. We observed that JNK inhibition in Aβ-injected rats can restore the activation of CREB through increasing its phosphorylation level. This effect may explain the increase observed in c-fos level, as a CREB downstream factor under JNK inhibition in Aβ-injected rats. Following Aβ injection, the levels of pro-survival mitochondrial proteins including nuclear respiratory factor-1 (NRF-1), peroxisome proliferator-activated receptor gamma co-activator 1-alpha, and mitochondrial transcription factor A (TFAM) significantly decreased, which could be returned to control level with JNK inhibition. We suggest that the elevation in the level of PGC1-alpha and other mitochondrial proteins is the result of an increase in CREB activation as the upstream factor of PGC1-alpha. Also, we observed that pretreatment with SP600125 leads to a greater increase of nuclear related factor-2 (Nrf2) level compared with the Aβ-injected group. Nrf2 has been shown to bind to CREB-binding factor leading to their contribution in Nrf2 target genes expression. Besides, NRF-1 and TFAM are reported as Nrf2 targets. Based on our data, we can conclude that JNK carry out partial destructive effects of Aβ in rat brain.
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ABSTRACT: Nrf2 (nuclear erythroid 2-related factor 2) is a basic region leucine-zipper transcription factor which binds to the antioxidant response element (ARE) and thereby regulates the expression of a large battery of genes involved in the cellular antioxidant and anti-inflammatory defence as well as mitochondrial protection. As oxidative stress, inflammation and mitochondrial dysfunctions have been identified as important pathomechanisms in amyotrophic lateral sclerosis (ALS), this signaling cascade has gained interest both with respect to ALS pathogenesis and therapy. Nrf2 and Keap1 expressions are reduced in motor neurons in postmortem ALS tissue. Nrf2-activating compounds have shown therapeutic efficacy in the ALS mouse model and other neurodegenerative disease models. Alterations in Nrf2 and Keap1 expression and dysregulation of the Nrf2/ARE signalling program could contribute to the chronic motor neuron degeneration in ALS and other neurodegenerative diseases. Therefore, Nrf2 emerges as a key neuroprotective molecule in neurodegenerative diseases. Our recent studies strongly support that the Nrf2/ARE signalling pathway is an important mediator of neuroprotection and therefore represents a promising target for development of novel therapies against ALS, Parkinson's disease (PD), Huntington's disease (HD), and Alzheimer's disease (AD).09/2012; 2012:878030. DOI:10.1155/2012/878030
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ABSTRACT: The endoplasmic reticulum (ER) lumen is chemically complex and crowded with polypeptides in different stages of assembly. ER quality control monitors chaperone-assisted protein folding, stochastic errors and off-pathway intermediates. In acute conditions, potentially toxic polypeptides overflow the capacity of the chaperone system and lead to ER stress. Activation of the unfolded protein response (UPR) following ER stress buys time for non-native polypeptides to refold or be eliminated; otherwise cell death occurs. The clearance routes for deleterious proteins are endoplasmic reticulum-associated degradation (ERAD) and ER stress-activated autophagy. The ERAD pathway is a chaperone and proteasome-mediated polypeptide degradation, while autophagy applies to wider range of substances. ER stress signal transduction recruits diverse molecules and pathways upon UPR induction to compensate stress condition. NF-E2-related factor 1 (Nrf1) and Nrf2 are two transcription factors mostly known by their induction through an antioxidant response; they can also be activated by UPR machinery. Discovery of diverse molecules downstream of Nrf1 and Nrf2 has expanded our understanding of the biological impacts of these transcription factors beyond classic antioxidant activation. In this review, we summarize our current understanding of mutual relationships between Nrf1, Nrf2, and ER stress clearance mechanisms and highlight the crosstalk of specific molecules mediating these correlations.Cellular and Molecular Life Sciences CMLS 06/2013; 70(24). DOI:10.1007/s00018-013-1409-y · 5.86 Impact Factor
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ABSTRACT: Alzheimer's disease (AD) is a neurodegenerative disorder characterized pathologically by the abnormal deposition of extracellular amyloid-β (Aβ) oligomers. However, the nature and precise mechanism of the toxicity of Aβ oligomers are not clearly understood. Aβ oligomers have been previously shown to cause a major loss of EphB2, a member of the EphB family of receptor tyrosine kinases. To determine the effect of EphB2 on Aβ oligomer-induced neurotoxicity and the underlying molecular mechanisms, we examined the EphB2 gene in cultured hippocampal neurons. Using a cellular model of AD, Aβ1-42 oligomers were confirmed to induce neurotoxicity in a time-dependent manner and result in a major decrease of EphB2. EphB2 overexpression could prevent the neurotoxicity of hippocampal neurons from exposure to Aβ1-42 oligomers for 1 h. Further analysis revealed that EphB2 overexpression increased synaptic NR1 and NR2B expression in Aβ1-42 oligomer-treated neurons. Moreover, EphB2 overexpression prevented Aβ1-42 oligomer-induced downregulation of dephosphorylated p38 MAPK and phosphorylated CREB. Together, these results suggest that EphB2 is a factor which protects hippocampal neurons against the toxicity of Aβ1-42 oligomers, and we infer that the protection of EphB2 is achieved by increasing the synaptic NMDA receptor level and downstream p38 MAPK and CREB signaling in hippocampal neurons. This study provides new molecular insights into the neuroprotective effect of EphB2 and highlights its potential therapeutic role in the management of AD.Neurochemistry International 07/2013; 63(4). DOI:10.1016/j.neuint.2013.06.016 · 2.65 Impact Factor