小胶质细胞在阿尔茨海默病发病机制中的作用

研究表明,β淀粉样蛋白(amyloid beta-peptide,Aβ)沉积激活小胶质细胞引起的炎症反应是阿尔茨海默病(Akheimer disease,AD)的核心病理机制之一,小胶质细胞在其发病机制中起着重要的作用。小胶质细胞被Ap激活,释放大量细胞因子和炎性介质,促进老年斑(senile plaques,SP)、神经原纤维缠结(neurofibrillary tangles,NFTs)的形成,导致神经元损伤、死亡,促使AD发生、发展。     

炎性因子与阿尔茨海默病发病关系

活化的胶质细胞介导的炎症反应在阿尔茨海默病（AD）发病中起重要作用,其产生的炎性因子可在胶质细胞、神经元和老年斑之间诱发炎症性级联反应,从而加重神经突和神经元损伤。目前,许多研究发现炎性因子基因多态性可影响其自身的表达量,且与AD的发生、发展有密切关系。该文就参与AD炎症反应的炎症细胞、炎性因子及其基因多态性与AD的关系进行综述。     

阿尔茨海默病患者的临床病理研究

目的 探讨阿尔茨海默病(AD)患者的临床病理特点,研究神经胶质细胞(NGCS)在脑内的分布及其在AD病理机制中的作用。方法 对8例临床诊断的AD患者和5例非痴呆老人(ND)的大脑皮层以及海马和杏仁核分别进行Bielschowsky氏浸银染色和Holzer氏磷钼酸结晶紫染色,并对老年斑(SPs)神经纤维缠结(NFTs)以及NGCs进行定量对照研究。结果 ①AD患者上述部位可见大量的SPs及细胞内、外NFTs和神经纤维毡丝(NTs),其分布各有不同,ND大脑上述病理改变的程度远无AD患者严重。②AD患者脑内可见明显的以小胶质细胞和星形胶质细胞为主的胶质增生反应,NGCs主要分布在SPs附近甚至核心,其数量和突起均明显多于ND大脑。③NGCs的分布与SPs(而不是NFTs)的分布似乎关系更为密切。结论 AD患者大脑内存在广泛的以NGCs增生和活跃为特征的慢性炎症反应,NGCs可能在AD病理机制中起重要作用。     

小胶质细胞在中枢神经系统创伤后的双重作用及调控机制

小胶质细胞是中枢神经系统的固有免疫细胞,在脑或脊髓创伤后的神经炎症反应中起关键作用。神经系统损伤后小胶质细胞可提供神经保护因子,清除细胞碎片并调控神经修补过程。而另一方面,小胶质细胞会产生高水平的促炎及细胞毒性介质从而阻碍CNS修复,促使神经元失能及细胞死亡。小胶质细胞的双重特性可能与其损伤后的表型及功能反应有关。本综述探讨近年来有关脑和脊髓损伤后小胶质细胞活化表型的研究,以及小胶质细胞在神经元、血管、少突胶质细胞生长及再生中的可能发挥的作用。并简述已知的调控表型转换的分子机制,着重探讨可以影响小胶质细胞活化状态的治疗途径。了解小胶质细胞表型调控机制有助于我们增加神经系统损伤恢复的知识,并提供新的治疗策略。     

小胶质细胞的概述及其与脑缺血的关系

炎症反应在脑缺血损伤中扮演着重要角色,主要表现在免疫细胞的激活,其中最主要的是小胶质细胞的激活。小胶质细胞的激活受到严格控制。脑缺血后小胶质细胞被激活,活化后的小胶质细胞形态和功能发生改变。小胶质细胞在脑缺血中发挥脑保护和神经毒性双重作用。因此,抑制小胶质细胞过度活化,拮抗神经毒性因子、促进神经保护因子、阻断小胶质细胞的炎症反应将为缺血性脑血管病的治疗提供新思路。     

京尼平对脂多糖诱导小胶质细胞炎症及凋亡的作用及机制研究

目的探讨京尼平(genipin)对脂多糖(LPS)诱导小胶质细胞(BV-2)炎症及凋亡反应的作用及机制。方法采用LPS诱导BV-2小胶质细胞建立中枢神经系统炎症和凋亡反应模型。实验细胞分为4组:空白对照组、京尼平组、LPS组、LPS+京尼平组。通过ELISA、RT-PCR、Western Blot、细胞流式检测细胞的炎症及凋亡反应。结果与空白对照组比较,LPS可以诱导BV-2细胞上清培养基中IL-6、IL-1β和TNF-α释放和细胞内IL-6、IL-1β和TNF-α转录的增加;同时,LPS还可以激活凋亡蛋白Bax并抑制抗凋亡蛋白Bcl-2的表达,导致细胞凋亡率的明显升高。京尼平预处理可以有效抑制小胶质细胞介导的炎症因子(IL-6、IL-1β和TNF-α)激活,并减少LPS诱导的小胶质细胞凋亡。结论 genipin干预可对LPS诱导的小胶质细胞炎症及凋亡反应起到保护作用。     

衰老小胶质细胞形态功能改变在帕金森病发病机制中的研究进展

帕金森病（Parkinson disease, PD）是一种衰老相关的神经退行性疾病，其发病机制尚不明确。已有研究表明小胶质细胞参与的神经炎症反应可能是PD发病的关键因素，但衰老小胶质细胞对PD发病及疾病进展的潜在影响尚未阐明。本文总结了衰老小胶质细胞在形态和功能方面的变化，并指出这些变化产生的促炎作用，分析了PD相关危险因素对小胶质细胞的衰老损害，初步探讨衰老小胶质细胞介导免疫失衡机制在PD的疾病过程中发挥的致病作用，并对靶向衰老小胶质细胞的潜在治疗手段进行简要综述。     

小胶质细胞在肌萎缩侧索硬化症研究中的作用

肌萎缩侧索硬化症(ALS)是以选择性运动神经元变性丢失、进行性瘫痪为特征的慢性退行性疾病,其相关发病机制学说众多,目前尚不明确。近年研究认为,运动神经元与其周围小胶质细胞的相互作用异常参与了ALS发病及病情进展,且小胶质细胞激活参与炎症反应在ALS发病中的作用越来越受到关注。此文就ALS发病中小胶质细胞的激活、作用以及可能作用机制做一综述,通过对小胶质细胞的调控可能为ALS治疗提供新的希望。     

纤维蛋白原对神经系统作用研究进展

纤维蛋白原是血液中存在的具有调节凝血、炎症及组织修复功能的多效蛋白.当神经系统外伤或疾病如脊髓损伤[1]、多发性硬化( multiple sclerosis,MS)[2]、缺血缺氧[3]、老年性痴呆( Alzheimer disease,AD)[4]等导致血管破裂、血脑屏障或血神经屏障破坏时,血液中可溶性纤维蛋白原渗入神经组织,立即在凝血酶作用下转化为不溶性纤维蛋白并在神经系统沉积,这可能会持续到损伤后数天,且与胶质瘢痕形成和炎症部位相关[5].纤维蛋白原进入脑组织可引起水肿及神经损害,并以配体的形式与胶质细胞、神经元及施万细胞受体相互作用诱导细胞特异性的信号通路活化从而调节炎症[6]、髓鞘再生和神经退行性病变[1,3].而且,纤维蛋白沉积与神经系统疾病存在时空相关性[5].因此,本文就纤维蛋白原在神经系统中的受体及功能作一综述.     

炎症与Alzheimer病

近年来研究表明,在Alzheimer病(AD)的病理过程中伴随着炎症和免症功能的变化。补体成分出现在老年斑周围,激活的小胶质细胞和细胞因子在老年斑中聚集、急性时相蛋白在血清中升高及在老年斑中沉淀等。本文旨在对炎症和免症机制在AD发病中的重要作用加以综述并为临床治疗提供线索。     

Utilizing pharmacotherapy and mesenchymal stem cell therapy to reduce inlfammation following traumatic brain injury

The pathologic process of chronic phase traumatic brain injury is associated with spreading inlfamma-tion, cell death, and neural dysfunction. It is thought that sequestration of inlfammatory mediators can facilitate recovery and promote an environment that fosters cellular regeneration. Studies have targeted post-traumatic brain injury inlfammation with the use of pharmacotherapy and cell therapy. These thera-peutic options are aimed at reducing the edematous and neurodegenerative inlfammation that have been associated with compromising the integrity of the blood-brain barrier. Although studies have yielded posi-tive results from anti-inlfammatory pharmacotherapy and cell therapy individually, emerging research has begun to target inlfammation using combination therapy. The joint use of anti-inlfammatory drugs along-side stem cell transplantation may provide better clinical outcomes for traumatic brain injury patients. Despite the promising results in this ifeld of research, it is important to note that most of the studies men-tioned in this review have completed their studies using animal models. Translation of this research into a clinical setting will require additional laboratory experiments and larger preclinical trials.     

肿瘤坏死因子基因多态性与脑血管病的关系研究进展

脑血管病的发生受环境和遗传等多方面因素影响,与炎性反应密切相关。肿瘤坏死因子 （tumor necrosis factor,TNF）作为一种促炎性因子,其基因多态性与脑血管病的关系受到人们的关注。 TNF不同基因型作为基因背景有可能决定了不同人群对疾病不同的易感性。TNF基因多态性在脑血管 发病中所起的作用,可能与其基因突变有关,但也可能存在多个位点相互协同或与其他炎症细胞因子 共同作用。本文对近年来有关TNF基因多态性与脑血管的关系研究进展进行综述,以便对脑血管病进 行风险预测、诊断及个体化治疗等方面的研究提供线索。     

Combination of methylprednisolone and rosiglitazone promotes recovery of neurological function atfer spinal cord injury

Methylprednisolone exhibits anti-inlfammatory antioxidant properties, and rosiglitazone acts as an anti-inlfammatory and antioxidant by activating peroxisome proliferator-activated receptor-γ in the spinal cord. Methylprednisolone and rosiglitazone have been clinically used during the early stages of secondary spinal cord injury. Because of the complexity and diversity of the inlfammatory process atfer spinal cord injury, a single drug cannot completely inhibit inlfammation. hTerefore, we assumed that a combination of methylprednisolone and rosiglitazone might promote recovery of neurological function atfer secondary spinal cord injury. In this study, rats were intraperitoneally injected with methylprednisolone (30 mg/kg) and rosiglitazone (2 mg/kg) at 1 hour atfer injury, and methylprednisolone (15 mg/kg) at 24 and 48 hours atfer injury. Rosiglitazone was then administered once every 12 hours for 7 consecutive days. Our results demonstrated that a combined treatment with methylprednisolone and rosiglitazone had a more pronounced effect on attenuation of inlfammation and cell apoptosis, as well as increased functional recovery, compared with either single treatment alone, indicating that a combination better pro-moted recovery of neurological function atfer injury.     

Hydroxycitric acid ameliorates inlfammation and oxidative stress in mouse models of multiple sclerosis

Hydroxycitric acid (HCA) is derived primarily from the Garcinia plant and is widely used for its anti-in-lfammatory effects. Multiple sclerosis can cause an inlfammatory demyelination and axonal damage. In this study, to validate the hypothesis that HCA exhibits therapeutic effects on multiple sclerosis, we established female C57BL/6 mouse models of multiple sclerosis,i.e., experimental autoimmune encephalomyelitis, using Complete Freund’s Adjuvant (CFA) emulsion containing myelin oligodendrocyte glycoprotein (35–55). Treatment with HCA at 2 g/kg/d for 3 weeks obviously improved the symptoms of nerve injury of experimental autoimmune encephalomyelitis mice, decreased serum interleulin-6, tumor necrosis factor alpha, nitric oxide, and malondialdehyde levels, and increased superoxide dismutase and glutathione reduc-tase activities. hTese ifndings suggest that HCA exhibits neuroprotective effects on multiple sclerosis-caused nerve injury through ameliorating inlfammation and oxidative stress.     

Oligodendrocyte ablation as a tool to study demyelinating diseases

Multiple sclerosis (MS) is an autoimmune mediated neurodegenerative disease characterized by demyelin-ation and oligodendrocyte (OL) loss in the central nervous system and accompanied by local inlfammation and inifltration of peripheral immune cells. Although many risk factors and symptoms have been iden-tified in MS, the pathology is complicated and the cause remains unknown. It is also unclear whether OL apoptosis precedes the inlfammation or whether the local inlfammation is the cause of OL death and demyelination. This review brielfy discusses several models that have been developed to speciifcally ablate oligodendrocytes in an effort to separate the effects of demyelination from inlfammation.     

Kynurenine pathway metabolism and neuroinlfammator y disease

Immune-mediated activation of tryptophan (TRYP) catabolism via the kynurenine pathway (KP) is a con-sistent ifnding in all inlfammatory disorders. Several studies by our group and others have examined the neurotoxic potential of neuroreactive TRYP metabolites, including quinolinic acid (QUIN) in neuroinlfam-matory neurological disorders, including Alzheimer’s disease (AD), multiple sclerosis, amylotropic lateral sclerosis (ALS), and AIDS related dementia complex (ADC). Our current work aims to determine whether there is any beneift to the affected individuals in enhancing the catabolism of TRYP via the KP during an immune response. Under physiological conditions, QUIN is metabolized to the essential pyridine nucle-otide, nicotinamide adenine dinucleotide (NAD+), which represents an important metabolic cofactor and electron transporter. NAD+also serves as a substrate for the DNA‘nick sensor’ and putative nuclear repair enzyme, poly(ADP-ribose) polymerase (PARP). Free radical initiated DNA damage, PARP activation and NAD+depletion may contribute to brain dysfunction and cell death in neuroinlfammatory disease.     

Clearing the corpses：regulatory mechanisms,novel tools,and therapeutic potential of harnessing microglial phagocytosis in the diseased brain

Apoptosis is a widespread phenomenon that occurs in the brain in both physiological and pathological conditions. Dead cells must be quickly removed to avoid the further toxic effects they exert in the pa-renchyma, a process executed by microglia, the brain professional phagocytes. Although phagocytosis is critical to maintain tissue homeostasis, it has long been either overlooked or indirectly assessed based on microglial morphology, expression of classical activation markers, or engulfment of artiifcial phagocytic targetsin vitro. Nevertheless, these indirect methods present several limitations and, thus, direct obser-vation and quantiifcation of microglial phagocytosis is still necessary to fully grasp its relevance in the diseased brain. To overcome these caveats and obtain a comprehensive, quantitative picture of microglial phagocytosis we have developed a novel set of parameters. hTese parameters have allowed us to identify the different strategies utilized by microglia to cope with apoptotic challenges induced by excitotoxicity or inlfammation. In contrast, we discovered that in mouse and human epilepsy microglia failed to ifnd and engulf apoptotic cells, resulting in accumulation of debris and inlfammation. Herein, we advocate that the effciency of microglial phagocytosis should be routinely tested in neurodegenerative and neuro-logical disorders, in order to determine the extent to which it contributes to apoptosis and inlfammation found in these conditions. Finally, our ifndings point towards enhancing microglial phagocytosis as a novel therapeutic strategy to control tissue damage and inlfammation, and accelerate recovery in brain diseases.     

Macrophage polarization in nerve injury: do Schwann cells play a role?

In response to peripheral nerve injury, the inflammatory response is almost entirely comprised of infiltrating macrophages. Macrophages are a highly plastic, heterogenic immune cell, playing an indispensable role in peripheral nerve injury, clearing debris and regulating the microenvironment to allow for efficient regeneration. There are several cells within the microenvironment that likely interact with macrophages to support their function – most notably the Schwann cell, the glial cell of the peripheral nervous system. Schwann cells express several ligands that are known to interact with receptors expressed by macrophages, yet the effects of Schwann cells in regulating macrophage phenotype remains largely unexplored. This review discusses macrophages in peripheral nerve injury and how Schwann cells may regulate their behavior.     

Examining the properties and therapeutic potential of glial restricted precursors in spinal cord injury

In the aftermath of spinal cord injury, glial restricted precursors (GRPs) and immature astrocytes offer the potential to modulate the inlfammatory environment of the injured spinal cord and promote host axon re-generation. Nevertheless clinical application of cellular therapy for the repair of spinal cord injury requires strict quality-assured protocols for large-scale production and preservation that necessitates long-term in vitro expansion. Importantly, such processes have the potential to alter the phenotypic and functional properties and thus therapeutic potential of these cells. Furthermore, clinical use of cellular therapies may be limited by the inlfammatory microenvironment of the injured spinal cord, altering the phenotypic and functional properties of grafted cells. This report simulates the process of large-scale GRP production and demonstrates the permissive properties of GRP following long-termin vitro culture. Furthermore, we de-ifned the phenotypic and functional properties of GRP in the presence of inlfammatory factors, and call attention to the importance of the microenvironment of grafted cells, underscoring the importance of modulating the environment of the injured spinal cord.     

蛛网膜下腔出血后迟发性脑血管痉挛的发病机制和治疗进展

脑血管痉挛（cerebral vasospasm,CVS）是蛛网膜下腔出血（subarochnoid hemorrhage,SAH）最 严重的并发症,尤其是迟发性脑血管痉挛（delayed cerebral vasospasm,DCV）,一旦发生可能会出现 脑缺血甚至死亡等严重并发症。目前其发病机制尚不明确,多种因素如红细胞分解产物、一氧化氮 （nitric oxide,NO）、内皮素、自由基和脂质过氧化物等均是导致DCV的重要因素,而对于治疗DCV的方 法也在持续探索中,SAH后DCV仍是目前面临的一大难题。本文主要对SAH后CVS的发病机制及治疗进 展进行综述。