小胶质细胞及其在阿尔茨海默病中的作用

阿尔茨海默病(AD)是一种常见的老年神经变性疾病,病因十分复杂。目前多数学者认为：β-淀粉样蛋白沉积使得神经胶质细胞活化引起脑内慢性炎症反应可能是AD发病的核心病理机制之一。在AD炎症过程中,渉及到诸多细胞如小胶质细胞、星形胶质细胞及神经元参与,小胶质细胞则是其最主要的炎症细胞,小胶质细胞被β-淀粉样蛋白（Aβ）激活,产生大量致炎性细胞因子和神经元毒性介质,从而诱发脑内炎症反应,导致神经元损伤、死亡。Aβ的持续存在,小胶质细胞被持续激活,形成炎症发生和持续的恶性循环,最后导致AD的发生发展。     

小胶质细胞在阿尔茨海默病神经炎性反应中作用的研究进展

阿尔茨海默病(AD)患者脑区存在不同分型的激活小胶质细胞。随神经炎性反应进展,这些细胞存在明显形态学和功能变化。它们通过改变细胞吞噬功能、参与免疫反应、或诱导胞内毒性反应来发挥致病作用。针对小胶质细胞在AD神经炎性反应中的作用,目前已开展一系列临床药物实验来推进靶向治疗。亟需更多研究来阐明小胶质细胞在AD神经炎性反应中的作用和机制。     

小胶质细胞在阿尔茨海默病中的作用及潜在的应用价值

<正>阿尔茨海默病(Alzheimer disease,AD)是神经退行性疾病的一种。全世界的痴呆症患者数约为5 000万,每年新增的痴呆症人数约为1 000万,AD是痴呆症中患病率最高的疾病,AD患者占痴呆症患者的60%～80%^[1]。AD的发病机制目前尚不明确,其病理特征主要为脑内β-淀粉样蛋白(amyloid β-protein,Aβ)聚集成的淀粉样斑块沉积和τ蛋白(tau protein)过度磷酸化产生的神经纤维缠结(neurofibrillary tangles,NFTs),     

上调自噬抑制LPS诱导的小胶质细胞死亡

目的:观察脂多糖(lipopolysaccharide,LPS)处理后,N9细胞自噬水平的变化,并探究LPS刺激下不同自噬水平对N9细胞的损伤和存活的影响。方法:体外培养N9细胞,给予24 h LPS处理,免疫荧光(IF)检测微管相关蛋白1轻链3(LC3)及溶酶体相关膜蛋白2(LAMP2)的表达,Western Blot检测LC3与Beclinl的表达。LPS处理后分别使用自噬诱导剂雷帕霉素(RAP)和自噬抑制剂3-甲基腺嘌呤(3-MA)调节N9细胞自噬水平,Western Blot检测不同处理组自噬标记蛋白LC3、Beclinl的表达;使用乳酸脱氢酶(lactic dehydrogenase)试剂盒、Cell Count Kit(CCK8)试剂盒检测细胞损伤及存活。结果:(1)LPS刺激造成N9细胞损伤,LDH释放量(113.6%±3.2%)较对照组(100.0%±3.9%)显著增加(P0.01),存活细胞数(69.8%±2.1%)较对照组(100.0%±3.9%)显著减少(P0.001);(2)与对照组相比,LPS显著上调N9细胞LC3以及Beclinl水平(P0.05)并同时上调LAMP2水平;(3)RAP上调LPS处理后N9细胞的自噬水平并减少小胶质细胞损伤(100.8%±2.3%),促进细胞存活(87.4%±5.7%)(P0.05)。3-MA则抑制LPS处理后N9细胞自噬水平并降低细胞存活(60.6%±2.9%),而细胞损伤(123.2%±3.7%)与LPS组相比未见统计学差异;(4)RAP与3-MA分别促进或抑制LPS诱导的N9细胞自噬相关蛋白的表达(P0.05)。结论:上调自噬水平减少LPS刺激诱导的N9细胞损伤,促进细胞存活。     

小胶质细胞在脑缺血再灌注损伤中的作用

炎症反应在脑缺血再灌注损伤机制中十分重要,而脑内小胶质细胞的激活是炎症反应中的重要环节.在脑缺血再灌注损伤过程中,小胶质细胞被激活,并对神经细胞发挥了损伤与保护双重作用.小胶质细胞对脑缺血再灌注损伤机制作用的复杂性,使其在脑缺血再灌注损伤研究中的意义也越来越受到重视.研究从小胶质细胞在脑缺血再灌注损伤后被激活参与炎症反应,与活化的小胶质细胞自身对脑缺血再灌注损伤的作用对小胶质细胞在脑缺血再灌注损伤中的双重作用很有意义.     

小胶质细胞吞噬在阿尔茨海默病不同阶段的作用及其机制

阿尔茨海默病(Alzheimer disease,AD)作为一种以进行性认知功能障碍和行为损害为主要临床表现的进行性中枢神经系统(central nervous system, CNS)变性疾病,在老龄化加速的现代社会越来越受到重视[1-2].AD的主要病理表现为β-淀粉样蛋白(amyloidβ-protein,Aβ)...     

小胶质细胞引起和促进阿尔茨海默病的研究进展

小胶质细胞是神经系统免疫细胞,具有双重特性,既可以通过免疫反应增强吞噬能力、释放抗炎因子维持脑组织的稳态和保护神经元,又可以增加炎性反应、降低有害蛋白清除能力损伤神经元.受衰老的影响,在基因表达方面,小胶质细胞CD33表达增加而髓系细胞触发受体2(TREM2)表达减少;在活化表型方面,衰老环境下的小胶质细胞更倾向活化为...     

自噬在非小细胞肺癌EGFR-TKIs治疗中的作用

自噬是一种应激细胞反应,其与耐药的产生密切相关。表皮生长因子受体酪氨酸激酶抑制剂(epidermal growth factor receptor-tyrosine kinase inhibitors,EGFR-TKIs)对EGFR突变的非小细胞肺癌(non-small cell lung cancer,NSCLC)患者有效;然而NSCLC的EGFR突变患者最终对EGFR-TKIs产生了耐药性。目前,自噬在EGFR-TKIs治疗中的作用尚存在争议,一方面,自噬抑制剂克服EGFR-TKIs的耐药性,增强了药物疗效;另一方面,自噬激活剂的使用促进了凋亡,从而增加药物疗效。该文着重对自噬在NSCLC的EGFR-TKIs治疗中的作用进行综述。     

小胶质细胞在脑缺血中的作用

19世纪末，Nissal首次描述了小胶质细胞。1919年，西班牙学Del Rino-Htortega用碳酸银染法将小胶质细胞与神经细胞及其它胶质细胞加以区分，推测小胶质细胞在胚胎早期源于中胚层的骨髓前期细胞，即单核吞噬系统。成年期，这些细胞位于中枢神经系统实质，成为小胶质细胞。这些观点现已普遍被人们所接受。根据细胞的形态，小胶质细胞有两种明显不同的亚型：分枝小胶质细胞和阿米巴样小胶质细胞。分枝小胶质细胞，其形态特征为胞体小，具有伸向各个方向的突起，在正常情况下，小胶质细胞为该型，     

A rationale for studying the transmissibility of Alzheimer's disease

—Despite extensive chemical, epidemiological, histopathological and pharmacological investigations of Alzheimer's disease (AD), its etiology remains elusive. This article describes studies supporting a rationale for exploring a transmissible slow viral etiology of at least some forms of AD. To date, a major limitation in these studies has been reliance upon induction of AD hispathology as the outcomes measure of successful transmission. Future studies should consider novel outcome measures for the detection of success although hispathologically inapparent, transmissible infection. In addition, the need to inoculate a diverse variety of rationally selected, potential hosts is stressed.     

ApoE4在阿尔茨海默病中的研究进展

载脂蛋白E(apolipoprotein E,ApoE)是一种脂质转运蛋白,在中枢神经系统的神经元中丰富表达,而ApoE4是其中的一种亚型.研究表明ApoE4是阿尔茨海默病(Alzheimer's disease,AD)的危险因素之一,会提高AD的发生率及降低其发病年龄.深入研究ApoE4的结构特性及在AD中的作用机制,有望使其成为诊治AD的靶点.     

Central amine metabolism in Alzheimer's disease: In vivo relationship to cognitive deficit

Levels of the amine metabolites homovanillic acid (HVA) and methoxyhydroxyphenylglycol (MHPG) were measured in the cerebrospinal (CSF) fluid of drug-free patients with Alzheimer's disease and compared to levels in a group of controls. No significant differences were found in CSF HVA and MHPG, although the Alzheimer's group was severely demented. Platelet monoamine oxidase (MAO) enzyme kinetics were measured and did not differ between controls and Alzheimer patients. The degree of dementia did not show any significant correlation with the levels of HVA or MHPG. It was concluded that, unlike previous reports in the literature, the dementia of Alzheimer's disease was not related to changes in central catecholamine metabolism nor was it associated with increased platelet MAO activity.     

Choline acetyltransferase immunohistochemistry in brains of alzheimer's disease patients and controls

Choline acetyltransferase (ChAT)-containing neuronal structures of the basal forebrain were studied by ChAT immunohistochemistry in the brains of persons dying with Alzheimer's disease (SDAT), as well as age-matched controls dying without neurological disorder. A loss of >50% in ChAT-containing neurons was found in the substantia innominata in the SDAT group. In contrast, there was no reduction in the number of ChAT-containing neurons of the putamen as compared with controls. The data confirm the reason for the reduction of ChAT as measured biochemically in the neocortex of SDAT cases, and support the cholinergic hypothesis of memory.     

与脐血多能干细胞共培养的小鼠淋巴细胞对AD小鼠的免疫调节作用

目的探讨与脐血多能干细胞(CB-SCs)共培养的淋巴细胞对阿尔兹海默病(AD)小鼠的免疫调节作用及治疗潜能。方法从人脐血中分离培养CB-SCs;从小鼠脾脏分离淋巴细胞;淋巴细胞与CB-SCs共同培养72 h或淋巴细胞单独培养;将AD小鼠随机分为实验组与对照组,实验组尾静脉注射与CB-SCs共培养的淋巴细胞,对照组尾静脉注射单独培养的淋巴细胞。注射结束后进行行为学实验,流式细胞学检测外周血淋巴细胞中调节性T细胞(Tregs)比例,ELISA检测小鼠外周血血浆中TNF-α和IL-10的表达,PCR检测AD小鼠脑内炎性因子的表达,免疫荧光染色检测AD小鼠脑内淀粉样斑块(β-amyloid,Aβ)含量。结果 1)实验组小鼠的空间学习记忆能力得到改善;2)实验组小鼠脑内的Aβ沉积量低于对照组;3)实验组外周血淋巴细胞中Tregs百分比及血浆中的抗炎因子IL-10浓度高于对照组(P0.05),而血浆中的促炎因子TNF-α浓度低于对照组(P0.001);4)实验组小鼠脑内IL-10的mRNA表达量高于对照组(P0.05),而TNF-α的mRNA表达量低于对照组(P0.05)。结论与脐血多能干细胞共培养的淋巴细胞对AD小鼠具有免疫治疗作用,主要通过增加Tregs细胞的比例并增强其抗炎功能来发挥作用。     

Computed tomography evaluations of brain-behavior relationships in senile d dementia of the Alzheimer's type

Neuropathological investigations have demonstrated brain-behavior relationships in senile dementia of the Alzheimer's type (SDAT), but CT studies have not produced consistent findings. We hypothesized that these discouraging results were in part due to limitations in the methods of CT scan evaluations, and to non-homogeneity of patient populations. The present study examined 43 out-patients with the presumptive diagnosis of SDAT using 37 cognitive test measures and 3 independent CT evaluation strategies. The CT methods included a new rank ordering procedure and two previously used techniques, physical measurement and 4-point rating. Highly significant (p≤0.01) brain-behavior correlations were attained using the ranking and rating procedures for evaluation of ventricular and cortical pathology. It was found that rank ordering has high interrater reliability and is superior to the other methods for the evaluation of the ventricular system. The physical measurement of the third ventricle is the single most powerful linear correlate of cognitive impairment. Measurement of cortical sulci are of no correlational significance. Multiple regression analyses indicated that global assessments are the best cognitive predictors of both ventricular and cortical pathology. Thus the present study has demonstrated brain-behavior relationships in vivo in SDAT.     

阿尔茨海默病患者照料者生命质量与主观幸福感的关系

目的:探讨阿尔茨海默病(AD)患者照料者主观幸福感与生命质量现状的关系,为AD患者照料者的干预研究提供理论支持。方法:采用健康测量量表(SF-36)、总体幸福感量表(GWB)对200名患者照料者进行调查。结果:(1)AD患者照料者的生命质量各维度得分与常模均有显著性差异,生理功能、生理职能、躯体疼痛、总体健康、活力、社会功能、情感职能、精神健康(t=-11.463,-12.487,-36.390,-10.801,-9.658,-25.556,-5.584,-13.298;P0.001)显著低于常模;(2)不同子女情况的AD患者照料者在生理功能、生理职能、总体健康、活力、社会功能、情感职能(t=-2.534,-7.205,-3.177,-3.397,-4.277,-4.591;P0.001)6个维度及生命质量总分(t=-9.608,P0.001)、主观幸福感总分(t=-2.613,P0.05)上差异具有显著性;(3)主观幸福感总分与生命质量总分、生理功能、生理职能、情感职能、总体健康(r=0.446,0.591,0.553,0.284,0.760;P0.01)均呈显著正相关;(4)主观幸福感得分可以显著预测生命质量量表总分(F=49.168,P0.001)。结论:(1)AD患者的生命质量状况低于全国水平;不同子女情况是影响AD患者照料者生命质量、主观幸福感的因素;(2)主观幸福感越强,AD患者照料者的生命质量水平越高。     

Neuroinflammatory phenotype in early Alzheimer's disease

Alzheimer's disease (AD) involves progressive neurodegeneration in the presence of misfolded proteins and poorly-understood inflammatory changes. However, research has shown that AD is genetically, clinically, and pathologically heterogeneous. In frozen brain samples of frontal cortex (diseased) and cerebellum (nondiseased) from the University of Kentucky Alzheimer's Disease Center autopsy cohort, we performed gene expression analysis for genes categorizing inflammatory states (termed M1 and M2) from early and late stage AD, and age-matched nondemented controls. We performed analysis of the serum samples for a profile of inflammatory proteins and examined the neuropathologic data on these samples. Striking heterogeneity was found in early AD. Specifically, early-stage AD brain samples indicated apparent polarization toward either the M1 or M2 brain inflammatory states when compared with age-matched nondisease control tissue. This polarization was observed in the frontal cortex and not in cerebellar tissue. We were able to detect differences in AD neuropathology, and changes in serum proteins that distinguished the individuals with apparent M1 versus M2 brain inflammatory polarization.     

阿尔茨海默病患者照料者生命质量与社会支持的关系

目的:探讨阿尔茨海默病(AD)患者照料者生命质量水平的现状以及影响生命质量的因素,反映AD患者照料者的身心健康水平,同时为AD患者照料者的相关研究提供理论依据。方法:采用健康测量量表(SF-36)、社会支持评定量表(SSRS)对200名AD患者照料者进行问卷调查。结果:(1)不同居住地的AD患者照料者在生理功能(t=-4.324,P0.001)、生理职能(t=-2.902,P0.01)、身体疼痛(t=3.918,P0.001)、总体健康(t=-4.041,P0.001)、社会支持各维度及社会支持总分(t=-5.787,P0.001)上存在差异;(2)与患者关系不同的AD患者照料者在生理功能(F=4.057,P0.05)、生理职能(F=6.808,P0.01)、身体疼痛(F=25.768,P0.001)、总体健康(F=8.448,P0.001)、活力(F=10.514,P0.001)、社会功能(F=3.235,P0.05)、精神健康(F=7.078,P0.01)、社会支持各维度上及社会支持总分(F=11.939,P0.001)、生命质量总分(F=3.531,P0.05)差异具有显著性;(3)不同家庭人均月收入的AD患者照料者在生命质量各维度(除精神健康)及社会支持总分(F=3.718~30.938,P0.001)上差异具有显著性;(4)社会支持得分与生命质量总分、生理职能、情感职能、总体健康、精神健康均呈显著正相关(r=0.315,0.361,0.243,0.384,0.283;P0.01)。结论:(1)AD患者照料者的生命质量、社会支持水平受居住地、与患者关系、家庭人均月收入的影响。(2)社会支持越强,AD患者照料者的生命质量水平越高。     

Measurement of cholinergic drug effects on memory in alzheimer's disease

Double-blind, placebo-controlled investigations of scopolamine, physostigmine, arecoline, and tetrahydroaminoacridine (THA) in normal adults and in dementia of the Alzheimer-type (DAT) were reviewed to determine the relative sensitivity of various assessment procedures in the measurement of drug effects. In normal adults, word list learning techniques have been most widely employed and have been sensitive to drug effects. In DAT, a wide variety of assessment procedures have been employed. Based on the limited number of possible comparisons across studies, two procedures appear to be useful: word list learning tasks that generate an index of intrusion errors, and visual recognition tasks. The lack of standardized assessments limits the ability of investigators to replicate studies, to compare relative efficacy of various drugs, or to address a number of other questions that are fundamental to the development of effective cholinergic treatments for DAT.