Intralumenal docking of connexin 36 channels in the ER isolates mistrafficked protein.

The intracellular domains of connexins are essential for the assembly of gap junctions. For connexin 36 (Cx36), the major neuronal connexin, it has been shown that a dysfunctional PDZ-binding motif interferes with electrical synapse formation. However, it is still unknown how this motif coordinates the transport of Cx36. In the present study, we characterize a phenotype of Cx36 mutants that lack a functional PDZ-binding motif using HEK293T cells as an expression system. We provide evidence that an intact PDZ-binding motif is critical for proper endoplasmic reticulum (ER) export of Cx36. Removing the PDZ-binding motif of Cx36 results in ER retention and the formation of multimembrane vesicles containing gap junction-like connexin aggregates. Using a combination of site-directed mutagenesis and electron micrographs, we reveal that these vesicles consist of Cx36 channels that docked prematurely in the ER. Our data suggest a model in which ER-retained Cx36 channels reshape the ER membrane into concentric whorls that are released into the cytoplasm.

Neural stem cell transplantation alleviates functional cognitive deficits in a mouse model of tauopathy.

The mechanisms of the transplantation of neural stem cells (NSCs) in the treatment of Alzheimer's disease remain poorly understood. In this study, NSCs were transplanted into the hippocampal CA1 region of the rTg (tau P301L) 4510 mouse model, a tauopathy model that is thought to reflect the tau pathology associated with Alzheimer's disease. The results revealed that NSC transplantation reduced the abnormal aggregation of tau, resulting in significant improvements in the short-term memory of the tauopathy model mice. Compared with wild-type and phosphate-buffered saline (PBS)-treated mice, mice that received NSC transplantations were characterized by changes in the expression of multiple proteins in brain tissue, particularly those related to the regulation of tau aggregation or misfolding. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and Gene Ontology (GO) function analysis revealed that these proteins were primarily enriched in pathways associated with long-term potentiation, neurogenesis, and other neurobiological processes. Changes in the expression levels of key proteins were verified by western blot assays. These data provided clues to improve the understanding of the functional capacity associated with NSC transplantation in Alzheimer's disease treatment. This study was approved by the Beijing Animal Ethics Association and Ethics Committee of Beijing Institute of Technology (approval No. SYXK-BIT-school of life science-2017-M03) in 2017.

The age-related microglial transformation in Alzheimer's disease pathogenesis.

Neuroinflammatory responses mediated by microglia, the resident immune cells of the central nervous system, have long been a subject of study in the field of Alzheimer's disease (AD). Microglia express a wide range of receptors that act as molecular sensors, through which they can fulfill their various functions. In this review, we first analyzed the changes in the expression levels of microglial membrane receptors SR-A, TREM2, CD36, CD33, and CR3 in aging and AD and described the different roles of these receptors in amyloid-beta clearance and inflammatory responses. Two classical hallmarks of AD are extracellular amyloid-beta deposits and intracellular aggregated phosphorylated tau. In AD, microglia reaction was initially thought to be triggered by amyloid deposits. New evidence showed it also associated with increased phosphorylation of tau. However, which first appeared and induced activated microglia is not clear. Then we summarized diverse opinions on it. Besides, as AD is tightly linked to aging, and microglia changes dramatically on aging, yet the relative impacts of both aging and microglia are less frequently considered, so at last, we discussed the roles of aging microglia in AD. We hope to provide a reference for subsequent research.

The Anti-Depression-Like Effects of Zhengtian Capsule via Induction of Neurogenesis and the Neurotrophic Signaling Pathway.

Oxidative stress that causes neural damages in neurodegenerative disorders has been widely studied for the pathogenesis and diagnostic measures. Zhengtian capsule (ZTC), a type of traditional Chinese medicine for headaches, has been found to have extra effects in recent years, such as promoting the release of serotonin and dopamine in the brain, but its specific mechanism has not been clearly elucidated. In this study, we focus on revealing whether ZTC can regulate key proteins of neurotrophic signaling pathway to alleviate depression-like behavior caused by oxidative stress. Experimental results show that ZTC (M 0.34 and H 0.7 g/kg) can elevate the proliferation of neural stem cells and GABAergic-type neurons in the hippocampus, promote the protein levels of BDNF, phosphorylated ERK1/2, and CREB, and inhibit the expression level of a key inflammation factor NFκB in a dose-dependent manner. These data suggest ZTC acts on multiple pathways to resist excessive oxidative stress, proving it to be a potential neurotrophic drug.

The Antioxidative Action of ZTP by Increasing Nrf2/ARE Signal Pathway.

So far, more than 25,000 brain diseases have been shown to be related to oxidative stress. Excessive free radicals and reactive oxygen species (ROS) can attack cells resulting in dysfunctional proteins, lipids, and nucleic acid, finally leading to imbalance of energy metabolism, cell death, gene mutation, and immune reaction. Therefore oxidative stress plays an important role in neuronal diseases. As a traditional Chinese medicine, Zhengtian Pill (ZTP) was reported to have the ability to reduce the blood viscosity of migraine model rats, with increased beta-endorphin, serotonin, adrenaline, and dopamine in brain tissue. Moreover ZTP can effectively accelerate blood circulation and attenuate blood coagulation. However, the molecular mechanisms of ZPT are still unclear. Through the behavioral test we found that ZTP can significantly improve depression-like behavior induced by LPS when rat was treated with ZTP (L 0.17 g/kg, M 0.34 g/kg, and H 0.7 g/kg) intraperitoneal injection once a day for 30 consecutive days. And ZTP can resist oxidative stress (>72 h) for a longer time. And ZTP can promote the levels of ATP and SOD and reduce the levels of ROS and MDA in the brain. At the same time, ZTP can have antioxidant stress through increasing the expression level of Nrf2/HO-1/P38. These results show that ZTP may be a potential antioxidant stress drug for variety of diseases associated with oxidative stress injury.