Glutamate versus GABA in neuron–oligodendroglia communication

In the central nervous system (CNS), myelin sheaths around axons are formed by glial cells named oligodendrocytes (OLs). In turn, OLs are generated by oligodendrocyte precursor cells (OPCs) during postnatal development and in adults, according to a process that depends on the proliferation and differentiation of these progenitors. The maturation of OL lineage cells as well as myelination by OLs are complex and highly regulated processes in the CNS. OPCs and OLs express an array of receptors for neurotransmitters, in particular for the two main CNS neurotransmitters glutamate and GABA, and are therefore endowed with the capacity to respond to neuronal activity. Initial studies in cell cultures demonstrated that both glutamate and GABA signaling mechanisms play important roles in OL lineage cell development and function. However, much remains to be learned about the communication of glutamatergic and GABAergic neurons with oligodendroglia in vivo. This review focuses on recent major advances in our understanding of the neuron–oligodendroglia communication mediated by glutamate and GABA in the CNS, and highlights the present controversies in the field. We discuss the expression, activation modes and potential roles of synaptic and extrasynaptic receptors along OL lineage progression. We review the properties of OPC synaptic connectivity with presynaptic glutamatergic and GABAergic neurons in the brain and consider the implication of glutamate and GABA signaling in activity-driven adaptive myelination.     

降钙素原、N前端脑钠肽、乳酸对评估ICU脓毒症患者预后价值的研究

目的探讨ICU脓毒症患者血浆降钙素原(PCT)、N前端脑钠肽(NT-pro-BNP)、乳酸(LAC)变化的临床意义及对预后评估的价值。 方法对2017年6月至2019年6月江苏大学附属金坛医院重症医学科(ICU)收治的脓毒症患者70例(观察组)和30例同期到院进行健康体检者(对照组)为研究对象进行前瞻性分析。脓毒症患者在初入ICU时抽取静脉血测定其PCT、NT-pro-BNP、LAC，对照组抽取空腹静脉血测定其PCT、NT-pro-BNP、LAC，比较上述两组指标的差异。观察组依据转归分为生存组、死亡组；比较不同转归患者PCT、NT-pro-BNP、LAC的差异。采用Spearman检验作生存死亡转归患者的PCT、NT-pro-BNP、LAC的相关性分析。应用ROC曲线评价PCT、NT-pro-BNP、LAC对脓毒症患者预后评估的价值。 结果观察组患者的PCT、NT-pro-BNP、LAC分别为(23.00±27.60)ng/L、(7 665.50±8 084.83)ng/L、(4.59±3.47)mg/L，较对照组增高，P均<0.05。死亡组患者的PCT、NT-pro-BNP、LAC分别为(45.65±30.64)ng/L、(9 950.21±7 118.21)ng/L、(6.79±3.00)mg/L，高于生存组，P均<0.05。Spearman相关性分析显示PCT、NT-pro-BNP、LAC与患者的生存转归呈负相关，r分别为-0.597、-0.323、-0.505，P均<0.05。ROC曲线显示：PCT的Cutoff值12.25 ng/L，灵敏度为0.998，特异度为0.698。NT-pro-BNP的Cutoff值2 372.50 ng/L，灵敏度为0.963，特异度为0.488。LAC的Cutoff值2.8 mg/L，灵敏度为0.999，特异度为0.628。 结论脓毒症患者PCT、NT-pro-BNP、LAC明显增高，联合检测PCT、NT-pro-BNP、LAC具有判断ICU脓毒症患者预后的价值。     

Elimination of amyloid precursor protein in senile plaques in the brain of a patient with Alzheimer-type dementia and Down syndrome

The average lifespan of individuals with Down syndrome has approximately doubled over the past three decades to 55–60?years. To reveal the pathogenic process of Alzheimer-type dementia in individuals with Down syndrome, we immunohistochemically examined senile plaque formation in the cerebral cortex in the autopsy brain and compared findings with our previous studies. We described a 52-year-old female with Down syndrome who developed progressively more frequent myoclonus following cognitive decline and died at the age of 59?years. Her karyotype [46XX, inv(9)(p12q13), i(21)(q10)] included triplication of the gene for amyloid precursor protein and the Down syndrome critical region. On microscopy, very few gamma-aminobutyric acid-ergic (GABAergic) neurons, in the form of small granular cells, in the cortex and Purkinje cells in the cerebellum were visible. In our previous study, amyloid precursor protein immunoreactivity was first noted in senile plaques at the age of 32?years. In this patient, even though amyloid β immunoreactivity was detected in the cores of senile plaques and diffuse plaques, amyloid precursor protein immunoreactivity was not noted in senile plaques in the frontal cortex. Amyloid precursor protein and its derivative amyloid-β play an important role in the formation of senile plaques and the time course of immunoreactive expression may be related to the pathogenic process of Alzheimer-type dementia.     

In vivo Ca2+ imaging of astrocytic microdomains reveals a critical role of the amyloid precursor protein for mitochondria

The investigation of amyloid precursor protein (APP) has been mainly confined to its neuronal functions, whereas very little is known about its physiological role in astrocytes. Astrocytes exhibit a particular morphology with slender extensions protruding from somata and primary branches. Along these fine extensions, spontaneous calcium transients occur in spatially restricted microdomains. Within these microdomains mitochondria are responsible for local energy supply and Ca²⁺ buffering. Using two-photon in vivo Ca²⁺ imaging, we report a significant decrease in the density of active microdomains, frequency of spontaneous Ca²⁺ transients and slower Ca²⁺ kinetics in mice lacking APP. Mechanistically, these changes could be potentially linked to mitochondrial malfunction as our in vivo and in vitro data revealed severe, APP-dependent structural mitochondrial fragmentation in astrocytes. Functionally, such mitochondria exhibited prolonged kinetics and morphology dependent signal size of ATP-induced Ca²⁺ transients. Our results highlight a prominent role of APP in the modulation of Ca²⁺ activity in astrocytic microdomains whose precise functioning is crucial for the reinforcement and modulation of synaptic function. This study provides novel insights in APP physiological functions which are important for the understanding of the effects of drugs validated in Alzheimer's disease treatment that affect the function of APP.     

缺血后处理对脑缺血大鼠学习记忆能力的影响

目的研究缺血后处理(IP)对大鼠脑缺血再灌注损伤后的学习和记忆能力的影响,探讨各组大鼠脑缺血再灌注后海马CA1区β淀粉样蛋白前体(APP)表达。方法将48只雄性SD大鼠随机分为3组:假手术组、对照组和缺血后处理组(IP组),每组16只大鼠。术后用Morris水迷宫方法测定大鼠认知记忆能力变化。3组大鼠脑组织切片行HE染色和APP染色,并行统计学分析。结果 Morris水迷宫试验显示,对照组大鼠训练第1~4天逃避潜伏期长于IP组(P 0. 01);跨越原平台次数IP组明显多于对照组(P 0. 05)。HE染色结果显示,对照组大鼠海马CA1区神经元细胞脱失明显,而IP可减轻这种形态学改变。免疫组化结果显示,在脑缺血再灌注144 h后对照组中APP表达明显高于假手术组(P 0. 01); IP组海马CA1区APP表达较对照组减少(P 0. 05)。结论缺血后处理可通过抑制APP的表达改善缺血再灌注后大鼠的记忆减退。     

急性中重度颅脑损伤患者血浆B型脑钠肽前体水平对患者CT临床特征的影响

目的 探讨急性中重度颅脑损伤患者血浆B型脑钠肽前体水平(BNP)对患者CT临床特征的影响,为临床辅助评估颅脑损伤病情提供参考.方法 选取2013年1月-2014年8月该院收治的发病24h以内的69例急性中重度颅脑损伤患者为研究对象,所有患者入院后立即行头颅CT扫描,记录所有患者的CT临床特征表现,并行Rotterdam CT评分,同时检测患者血浆BNP水平,另外同期选取70例健康体检者为对照组做对照,分析血浆BNP水平对患者CT临床特征表现的影响.结果 颅脑损伤患者血浆BNP水平明显高于对照组(P＜0.05);CT检查临床特征表现中具有基底池完全闭塞、中线移位＞5mm、脑室受压比值≤0.2、伴有蛛网膜下腔出血、Rotterdam CT评分＞3分与血浆高水平BNP密切相关(P＜0.05);在血浆BNP高分组(BNP≥179.48pg/ml)组患者CT检查临床特征表现中,基底池情况及中线移位评分、Rotterdam CT评分、蛛网膜下腔出血的发生率高于低水平组(P＜0.05),而脑室受压比值及GSC评分小于低水平组(P＜0.05);相关分析提示血浆BNP水平与RotterdamCT评分、中线移位、基底池情况分级呈正相关(P＜0.05),而与脑室受压比值GSC评分呈负相关(P＜0.05);多因素Logistic回归分析显示:血浆BNP水平(OR=2.421,P＜0.05)是Rotterdam CT评分＞3分的独立预测因素.结论 血浆BNP水平对急性中重度颅脑损伤患者CT检查中不同临床特征表现有一定影响,并且与Rotterdam CT评分密切相关,有利于辅诊科室评估中重度颅脑损伤患者的病情严重程度并作出相应的影像学诊断.     

Discovery of nitazoxanide-based derivatives as autophagy activators for the treatment of Alzheimer's disease

Drug repurposing is an efficient strategy for new drug discovery. Our latest study found that nitazoxanide (NTZ), an approved anti-parasite drug, was an autophagy activator and could alleviate the symptom of Alzheimer's disease (AD). In order to further improve the efficacy and discover new chemical entities, a series of NTZ-based derivatives were designed, synthesized, and evaluated as autophagy activator against AD. All compounds were screened by the inhibition of phosphorylation of p70S6K, which was the direct substrate of mammalian target of rapamycin (mTOR) and its phosphorylation level could reflect the mTOR-dependent autophagy level. Among these analogs, compound 22 exhibited excellent potency in promoting β-amyloid (Aβ) clearance, inhibiting tau phosphorylation, as well as stimulating autophagy both in vitro and in vivo. What's more, 22 could effectively improve the memory and cognitive impairments in APP/PS1 transgenic AD model mice. These results demonstrated that 22 was a potential candidate for the treatment of AD.     

Differential effects of glucose deprivation on the survival of fetal versus adult neural stem cells-derived oligodendrocyte precursor cells

Impaired myelination is a key feature in neonatal hypoxia/ischemia (HI), the most common perinatal/neonatal cause of death and permanent disabilities, which is triggered by the establishment of an inflammatory and hypoxic environment during the most critical period of myelin development. This process is dependent on oligodendrocyte precursor cells (OPCs) and their capability to differentiate into mature oligodendrocytes. In this study, we investigated the vulnerability of fetal and adult OPCs derived from neural stem cells (NSCs) to inflammatory and HI insults. The resulting OPCs/astrocytes cultures were exposed to cytokines to mimic inflammation, or to oxygen–glucose deprivation (OGD) to mimic an HI condition. The differentiation of both fetal and adult OPCs is completely abolished following exposure to inflammatory cytokines, while only fetal-derived OPCs degenerate when exposed to OGD. We then investigated possible mechanisms involved in OGD-mediated toxicity: (a) T3-mediated maturation induction; (b) glutamate excitotoxicity; (c) glucose metabolism. We found that while no substantial differences were observed in T3 intracellular content regulation and glutamate-mediated toxicity, glucose deprivation lead to selective OPC cell death and impaired differentiation in fetal cultures only. These results indicate that the biological response of OPCs to inflammation and demyelination is different in fetal and adult cells, and that the glucose metabolism perturbation in fetal central nervous system (CNS) may significantly contribute to neonatal pathologies. An understanding of the underlying molecular mechanism will contribute greatly to differentiating myelination enhancing and neuroprotective therapies for neonatal and adult CNS white matter lesions.