Activation of α7 nicotinic acetylcholine receptor alleviates Aß1-42-induced neurotoxicity via downregulation of p38 and JNK MAPK signaling pathways.

Amyloid ß peptide 1-42 (Aß1-42) could induce cognitive deficits through oxidative stress, inflammation, and neuron death in Alzheimer's disease (AD). MAPK pathways have been thought to mediate Aß1-42-induced neuroinflammation responses, neuron death and cognitive decline in AD. The α7 nicotinic acetylcholine receptor (α7nAChR) exerts a neuroprotective effect. However, whether α7nAChR alleviates Aß1-42-induced neurotoxicity through MAPKs (p38, ERK, JNK) in vivo remains unclear. In our study, memory was assessed in C57BL/6 mice using a Y-maze test. Cell death was assessed by Nissl and Hoechst staining and Bax, Bcl-2, Caspase 3, and Cytochrome C levels using Western blotting. Oxidative stress was assayed by superoxide dismutase (SOD), catalase (CAT), and malondialdehyde (MDA) levels. Inflammation was examined with GFAP and Iba1 using immunohistochemistry. The Aß degrading enzymes insulin degrading enzyme (IDE) and neprilysin (NEP) were tested using Western blotting. We found that activating α7nAChR or inhibiting p38 or JNK pathway alleviated Aß1-42-induced cognitive deficits and neuron loss and death by reducing oxidative stress. In addition, activating α7nAChR or inhibiting p38 or JNK pathway also reduced inflammation, which was observed as reduced GFAP and Iba1 levels with different effects on Aß degrading enzymes. Finally, we found that the activation of α7nAChR led to the downregulation of pp38 and pJNK levels. Conversely, the inhibition of p38 or JNK resulted in the upregulation of α7nAChR levels in the hippocampus and cortex. Our data indicate that the activation of α7nAChR alleviates Aß1-42-induced neurotoxicity, and this protective effect might act through the downregulation of p38 and JNK MAPKs.

The p38 mitogen activated protein kinase regulates ß-amyloid protein internalization through the α7 nicotinic acetylcholine receptor in mouse brain.

Alzheimer's disease (AD) is one of the most devastating neurodegenerative disorders. Intracellular ß-amyloid protein (Aß) is an early event in AD. It induces the formation of amyloid plaques and neuron damage. The α7 nicotinic acetylcholine receptor (α7nAChR) has been suggested to play an important role in Aß caused cognition. It has high affinity with Aß and could mediate Aß internalization in vitro. However, whether in mouse brain the p38 MAPK signaling pathway is involved in the regulation of the α7nAChR mediated Aß internalization and their role in mitochondria remains little known. Therefore, in this study, we revealed that Aß is internalized by cholinergic and GABAergic neurons. The internalized Aß were found deposits in lysosomes/endosomes and mitochondria. Aß could form Aß-α7nAChR complex with α7nAChR, activates the p38 mitogen activated protein kinase (MAPK). And the increasing of α7nAChR could in return mediate Aß internalization in the cortex and hippocampus. In addition, by using the α7nAChR agonist PNU282987, the p38 phosphorylation level decreases, rescues the biochemical changes which are tightly associated with Aß-induced apoptosis, such as Bcl2/Bax level, cytochrome c (Cyt c) release. Collectively, the p38 MAPK signaling pathway could regulate the α7nAChR-mediated internalization of Aß. The activation of α7nAChR or the inhibition of p38 MAPK signaling pathway may be a beneficial therapy to AD.

[Evaluation of Temporal and Spatial Variation Characteristics of Nutrients in Surface Sediment in the Three Gorges Reservoir Area].

With the construction of the Three Gorges Dam, the river flow pattern and sediment dynamics are expected to be affected. As a consequence, the sediment traits could be impacted by these changes. The temporal and spatial variation characteristics of the nutrient content from 2000 to 2015 in surface sediment were analyzed in the main stream from Jiangjin to the dam site section of the Yangtze River and in the estuaries of the representative input tributaries of the Three Gorges Reservoir, such as the Jialing River, Yulin River, Wujiang River, Xiaojiang River, Daning River, and Xiangxi River. Then, the state of the pollution was assessed. Results revealed that the average concentrations of total phosphorus (TP) in the surface sediments of the main stream ranged from 678.2 to 928.6 mg·kg-1, the average contents of total nitrogen (TN) ranged from 0.203% to 0.362%, the average contents of potassium ranged from 1.74% to 2.37%, and the average contents of organic matter ranged from 0.94% to 1.54%. The average concentrations of TP in the estuaries of the representative input tributaries ranged from 490.1 to 832.3 mg·kg-1, the average contents of TN ranged from 0.257% to 0.495%, the average contents of potassium ranged from 1.69% to 2.32%, and the average contents of organic matter ranged from 1.21% to 2.27%. The concentrations of TP and potassium in the study sections were generally within background concentration ranges, while the concentrations of TN were obviously above background levels, and the concentrations of organic matter were obviously below background levels. The nutrient contents in the surface sediment did not display significant differences among the study sites; however, the distributions of different nutrient contents along the river varied widely. Although the nutrient contents in the surface sediments fluctuated somewhat during different flow periods, they were seemingly unaffected by the impoundment, since no obvious enrichment was observed throughout the impoundment. The evaluation of organic index indicated a clean state for the surface sediments in the majority of the study area, while there was a moderately polluted state in some local sections. The evaluation of nitrogen pollution indicated a polluted state for most sections. Overall, the nutrients in the surface sediments of the Three Gorges Reservoir showed moderate ecological risks, possibly caused by TP and TN.