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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Abbreviations
- Aβ:
-
Amyloid-beta
- AD:
-
Alzheimer’s disease
- APP:
-
Amyloid precursor protein
- AREs:
-
Antioxidant response elements
- CBP:
-
CREB-binding protein
- CREB:
-
cAMP response element-binding
- DMSO:
-
Dimethyl sulfoxide
- ECL:
-
Electrochemiluminescence
- ER:
-
Endoplasmic reticulum
- HO-1:
-
Heme oxygenase-1
- i.c.v.:
-
Intracerebroventricular
- JNKs:
-
c-Jun N-terminal kinases
- MAPKs:
-
Mitogen-activated protein kinases
- NRF-1:
-
Nuclear respiratory factor-1
- Nrf2:
-
Nuclear related factor-2
- PBS:
-
Phosphate buffer saline
- PGC-1α:
-
Peroxisome proliferator-activated receptor gamma co-activator 1-alpha
- TFAM:
-
Mitochondrial transcription factor A
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This work was supported by Shahid Beheshti University of Medical Sciences Research Funds.
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Yenki, P., Khodagholi, F. & Shaerzadeh, F. Inhibition of Phosphorylation of JNK Suppresses Aβ-Induced ER Stress and Upregulates Prosurvival Mitochondrial Proteins in Rat Hippocampus. J Mol Neurosci 49, 262–269 (2013). https://doi.org/10.1007/s12031-012-9837-y
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DOI: https://doi.org/10.1007/s12031-012-9837-y