小胶质细胞极化与抑郁症关系的研究进展

小胶质细胞控制着中枢神经系统主要的免疫功能,在各种精神疾病中发挥重要作用. 某些信号通路的激活引发的神经炎症与抑郁症的发生有着密切的关系. 小胶质细胞是神经炎症的主要介导者,不同的刺激促进小胶质细胞极化,不同极化类型的小胶质细胞能分泌多种炎性细胞因子,在神经炎症调节中具有重要的作用. 临床研究和体内外实验研究表明,抑郁症与小胶质细胞极化介导的神经炎症有关. 小胶质细胞极化参与抑郁症发生发展的可能机制包括NF-κB信号通路激活、呼吸爆发、补体受体3信号通路、NLRP3炎症激活、cannibalism受体1、Notch-1信号通路和过氧化物酶体增殖物激活受体γ的激活. 本文就小胶质细胞极化与抑郁关系的研究进展作一综述.     

阿尔茨海默病中β淀粉样蛋白的生成及清除的调节

阿尔茨海默病（Alzheimer’s disease, AD）是一种慢性退行性神经系统疾病,临床主要表现为进行性认知能力下降、记忆力衰退、人格改变等。AD的标志性病理特征包括脑细胞外β淀粉样蛋白（β-amyloid protein,Aβ）沉积形成老年斑、细胞内神经纤维缠结(neurofibrillary tangles,NFT)、神经炎症增加以及神经元凋亡。β淀粉样蛋白主要在神经元产生,是淀粉样前体蛋白经过一系列酶解反应生成的由39～42个氨基酸组成的多肽,调节Aβ的生成和清除能够有效延缓甚至逆转阿尔茨海默病的进程,因而具有重大的研究价值。β-分泌酶（β-site APP cleaving enzyme 1,BACE1）为Aβ产生过程中的关键酶,其含量及活性的改变均能影响Aβ产生,在阿尔茨海默病的发生发展中发挥至关重要的作用;老年斑周围炎性细胞的聚集提示,AD与神经炎症高度相关,神经炎症相关细胞能够参与Aβ的清除,多种炎性因子也能调节Aβ的生成;非编码RNA虽很少直接参与Aβ的产生、沉积和清除,但其可以通过多种途径调节Aβ的产生。本文从β淀粉样蛋白生成及清除的机制着手,重点阐述了BACE1、神经炎症、非编码RNA对Aβ调控的重要作用,以期为AD发病机制的进一步研究提供思路,并对阿尔茨海默病早期干预及治疗提供理论参考。     

Oridonin ameliorates neuropathological changes and behavioural deficits in a mouse model of cerebral amyloidosis

Alzheimer's disease (AD) is the most common form of neurodegeneration and the major cause of dementia. This multifactorial disorder is clinically defined by progressive behavioural and cognitive deficits, and neuropathologically characterized by β‐amyloid aggregation, hyperphosphorylated tau and neuroinflammation. Oridonin, a diterpenoid isolated from Chinese herb Rabdosia rubescens, has multiple biological properties, especially anti‐inflammatory and neuroregulatory activities. Potential therapeutic effects of Oridonin were investigated in an animal model of cerebral amyloidosis for AD, transgenic APP/PS1 mice. Oridonin was suspended in carboxymethylcellulose or loaded with a nanostructured emulsion, and was orally administrated or injected. Before, during and following the experimental treatments, behavioural tests were performed with these transgenic mice and their naive littermates. Following relatively short‐term treatments of 10 days, brain tissue of mice were removed for immunohistochemical assays. The results indicate that both oral treatment and injection of Oridonin significantly attenuated β‐amyloid deposition, plaque‐associated APP expression and microglial activation in brain of transgenic mice. Furthermore, injection of Oridonin‐nanoemulsion ameliorated deficits in nesting, an important affiliative behaviour, and in social interaction. Additional in vitro studies indicated that Oridonin effectively attenuated inflammatory reaction of macrophage and microglial cell lines. Our results suggest that Oridonin might be considered a promising therapeutic option for human AD or other neurodegenerative diseases.     

miR-194 relieve neuropathic pain and prevent neuroinflammation via targeting FOXA1

The emerging role of microRNAs (miRNAs) have been deeply explored in multiple diseases including neuropathic pain. miR-194 was widely reported to be a tumor suppressor and was related to the inflammatory response. The critical role of neuroinflammation on neuropathic pain leads to a thinking about the relationship between miR-194 and neuropathic pain. However, the function of miR-194 in neuropathic pain remains unknown. This study was aimed to explore the relationship between miR-194 and neuropathic pain progression by chronic sciatic nerve injury (CCI). miR-194 abnormally downregulated in the CCI model rat and its overexpression significantly alleviates neuroinflammation in vivo. We predict Forkhead box protein A1 (FOXA1) as a direct target of miR-194, whose restoration can markedly reverse the effects of miR-194 on neuropathic pain. Overall, our study demonstrated a novel mechanism of neuropathic pain progression that miR-194 alleviates neuropathic pain via targeting FOXA1 and preventing neuroinflammation by downregulating inflammatory cytokines containing cyclooxygenase 2, interleukin 6 (IL-6), and IL-10 in vivo, which can be reversed by the overexpression of FOXA1.     

Improved Methodology for Sensitive and Rapid Quantitative Proteomic Analysis of Adult‐Derived Mouse Microglia: Application to a Novel In Vitro Mouse Microglial Cell Model

Microglia, as the resident brain immune cells, can exhibit a broad range of activation phenotypes, which have been implicated in a multitude of central nervous system disorders. Current widely studied microglial cell lines are mainly derived from neonatal rodent brain that can limit their relevance to homeostatic function and disease‐related neuroimmune responses in the adult brain. Recently, an adult mouse brain‐derived microglial cell line has been established; however, a comprehensive proteome dataset remains lacking. Here, an optimization method for sensitive and rapid quantitative proteomic analysis of microglia is described that involves suspension trapping (S‐Trap) for efficient and reproducible protein extraction from a limited number of microglial cells expected from an adult mouse brain (≈300 000). Using a 2‐h gradient on a 75‐cm UPLC column with a modified data dependent acquisition method on a hybrid quadrupole‐Orbitrap mass spectrometer, 4855 total proteins have been identified where 4698 of which are quantifiable by label‐free quantitation with a median and average coefficient of variation (CV) of 6.7% and 10.6%, respectively. This dataset highlights the high depth of proteome coverage and related quantitation precision of the adult‐derived microglial proteome including proteins associated with several key pathways related to immune response. Data are available via ProteomeXchange with identifier PXD012006.     

Emerging roles of long non‐coding RNAs in neuropathic pain

Neuropathic pain, a type of chronic and potentially disabling pain resulting from primary injury/dysfunction of the somatosensory nervous system and spinal cord injury, is one of the most intense types of chronic pain, which incurs a significant economic and public health burden. However, our understanding of its cellular and molecular pathogenesis is still far from complete. Long non‐coding RNAs (lncRNAs) are important regulators of gene expression and have recently been characterized as key modulators of neuronal functions. Emerging evidence suggested that lncRNAs are deregulated and play pivotal roles in the development of neuropathic pain. This review summarizes the current knowledge about the roles of deregulated lncRNAs (eg, KCNA2‐AS, uc.48+, NONRATT021972, MRAK009713, XIST, CCAT1) in the development of neuropathic pain. These studies suggested that specific regulation of lncRNAs or their downstream targets might provide novel therapeutic avenues for this refractory disease.