慢性脑低灌注性血管性认知损害患者血清p75神经营养素受体细胞外段水平及其与炎性因子的关系

目的检测慢性脑低灌注性血管性认知损害(CCH-VCI)患者血清p75神经营养素受体细胞外段(p75NTR-ECD)水平,并探讨其与肿瘤坏死因子α(TNF-α)、白细胞介素(IL)-1β、IL-6的关系。方法选择海军军医大学(第二军医大学)长海医院2018年8月至12月收治的34例CCH-VCI患者,以及同期相同年龄段的36名中老年健康人和34例缺血性脑卒中患者作为研究对象。采用酶联免疫吸附试验测定3组研究对象的血清p75NTR-ECD、TNF-α、IL-1β、IL-6水平并进行组间比较。采用Spearman相关分析研究CCH-VCI患者血清p75NTR-ECD水平与TNF-α、IL-1β、IL-6水平的相关性。结果CCH-VCI组血清p75NTR-ECD水平高于健康对照组和缺血性脑卒中组[(544.36(440.88,628.50)pg/mL vs 276.49(262.59,313.87)pg/mL、366.87(337.09,450.43)pg/mL],差异均有统计学意义(U=87.500、335.500,P均<0.05)。CCH-VCI组患者血清TNF-α、IL-1β、IL-6水平分别为196.02(141.20,280.35)pg/mL、68.23(60.79,91.94)pg/mL、51.04(40.24,65.26)pg/mL,缺血性脑卒中组分别为218.67(143.76,281.28)pg/mL、76.87(59.10,99.91)pg/mL、64.45(43.13,86.76)pg/mL,均分别高于健康对照组[分别为73.71(56.94,79.81)pg/mL、42.98(34.52,51.34)pg/mL、14.97(11.76,21.19)pg/mL],差异均有统计学意义(U=31.000、4.000,106.000、132.000,48.000、13.000;P均<0.05)。CCH-VCI患者血清p75NTR-ECD水平与TNF-α水平存在相关性(r=0.391,P=0.022),但与IL-1β和IL-6水平均无明显相关性(r=0.032、0.164,P=0.855、0.355)。结论慢性脑低灌注损伤后p75NTR可能与TNF-α等炎性因子有关,并共同参与了CCH-VCI的发病。

Axonal growth inhibitors and their receptors in spinal cord injury:from biology to clinical translation

Axonal growth inhibitors are released during traumatic injuries to the adult mammalian central nervous system, including after spinal cord injury. These molecules accumulate at the injury site and form a highly inhibitory environment for axonal regeneration. Among these inhibitory molecules, myelinassociated inhibitors, including neurite outgrowth inhibitor A, oligodendrocyte myelin glycoprotein, myelin-associated glycoprotein, chondroitin sulfate proteoglycans and repulsive guidance molecule A are of particular importance. Due to their inhibitory nature, they represent exciting molecular targets to study axonal inhibition and regeneration after central injuries. These molecules are mainly produced by neurons, oligodendrocytes, and astrocytes within the scar and in its immediate vicinity. They exert their effects by binding to specific receptors, localized in the membranes of neurons. Receptors for these inhibitory cues include Nogo receptor 1, leucine-rich repeat, and Ig domain containing 1 and p75 neurotrophin receptor/tumor necrosis factor receptor superfamily member 19(that form a receptor complex that binds all myelin-associated inhibitors), and also paired immunoglobulin-like receptor B. Chondroitin sulfate proteoglycans and repulsive guidance molecule A bind to Nogo receptor 1, Nogo receptor 3, receptor protein tyrosine phosphatase σ and leucocyte common antigen related phosphatase, and neogenin, respectively. Once activated, these receptors initiate downstream signaling pathways, the most common amongst them being the Rho A/ROCK signaling pathway. These signaling cascades result in actin depolymerization, neurite outgrowth inhibition, and failure to regenerate after spinal cord injury. Currently, there are no approved pharmacological treatments to overcome spinal cord injuries other than physical rehabilitation and management of the array of symptoms brought on by spinal cord injuries. However, several novel therapies aiming to modulate these inhibitory proteins and/or their receptors are under investigation in ongoing clinical trials. Investigation has also been demonstrating that combinatorial therapies of growth inhibitors with other therapies, such as growth factors or stem-cell therapies, produce stronger results and their potential application in the clinics opens new venues in spinal cord injury treatment.

Elevated Levels of Naturally-Occurring Autoantibodies Against the Extracellular Domain of p75NTR Aggravate the Pathology of Alzheimer's Disease

The extracellular domain(p75ECD)of p75 neurotrophin receptor(p75NTR)antagonizes Aβ neurotoxicity and promotes Aβclearance in Alzheimer’s disease(AD).The impaired shedding of p75ECD is a key pathological process in AD,but its regulatory mechanism is largely unknown.This study was designed to investigate the presence and alterations of naturally-occurring autoantibodies against p75ECD(p75ECD-NAbs)in AD patients and their effects on AD pathology.We found that the cerebrospinal fluid(CSF)level of p75ECD-NAbs was increased in AD,and negatively associated with the CSF levels of p75ECD.Transgenic AD mice actively immunized with p75ECD showed a lower level of p75ECD and more severe AD pathology in the brain,as well as worse cognitive functions than the control groups,which were immunized with Re-p75ECD(the reverse sequence of p75ECD)and phosphate-buffered saline,respectively.These findings demonstrate the impact of p75ECD-NAbs on p75NTR/p75ECD imbalance,providing a novel insight into the role of autoimmunity and p75NTR in AD.

p75神经营养因子受体胞外域在阿尔茨海默病防治中的研究进展

阿尔茨海默病(Alzheimer′s disease,AD)是一种主要表现为伴随进行性记忆丧失的认知功能障碍和行为障碍的神经退行性疾病,目前还未发现能够治愈AD的有效方法或药物。近年来研究发现p75神经营养因子受体(p75NTR)在AD的发病过程中起重要作用,而p75NTR的胞外域(p75ECD)具有神经保护作用,能减缓AD的病理进程,成为AD防治中一个潜在的具有前景的研究靶点。本文综述了近年来关于p75ECD在AD防治中的相关研究,以便研究者掌握目前研究进展,为开发新的治疗阿尔茨海默病的方法和药物提供参考和依据。