BACKGROUND & AIMS: :Microglial dysfunction is a key pathological feature of Alzheimer's disease (AD), but little is known about proteome-wide changes in microglia during the course of AD and their functional consequences. Here, we performed an in-depth and time-resolved proteomic characterization of microglia in two mouse models of amyloid β (Aβ) pathology, the overexpression APPPS1 and the knock-in APP-NL-G-F (APP-KI) model. We identified a large panel of Microglial Aβ Response Proteins (MARPs) that reflect heterogeneity of microglial alterations during early, middle and advanced stages of Aβ deposition and occur earlier in the APPPS1 mice. Strikingly, the kinetic differences in proteomic profiles correlated with the presence of fibrillar Aβ, rather than dystrophic neurites, suggesting that fibrillar Aβ may trigger the AD-associated microglial phenotype and the observed functional decline. The identified microglial proteomic fingerprints of AD provide a valuable resource for functional studies of novel molecular targets and potential biomarkers for monitoring AD progression or therapeutic efficacy. :Alzheimer’s disease is a progressive, irreversible brain disorder. Patients with Alzheimer’s have problems with memory and other mental skills, which lead to more severe cognitive decline and, eventually, premature death. This is due to increasing numbers of nerve cells in the brain dying over time. A distinctive feature of Alzheimer’s is the abnormally high accumulation of a protein called amyloid-β, which forms distinctive clumps in the brain termed ‘plaques’. The brain has a type of cells called the microglia that identify infections, toxic material and damaged cells, and prevent these from building up by clearing them away. In Alzheimer’s disease, however, the microglia do not work properly, which is thought to contribute to the accumulation of amyloid-β plaques. This means that people with mutations in the genes important for the microglia activity are also at higher risk of developing the disease. Although problems with the microglia play an important role in Alzheimer’s, researchers still do not fully understand why microglia stop working in the first place. It is also not known exactly when and how the microglia change as Alzheimer’s disease progresses. To unravel this mystery, Sebastian Monasor, Müller et al. carried out a detailed study of the molecular ‘fingerprints’ of microglia at each key stage of Alzheimer’s disease. The experiments used microglia cells from two different strains of genetically altered mice, both of which develop the hallmarks of Alzheimer’s disease, including amyloid-β plaques, at similar rates. Analysis of the proteins in microglia cells from both strains revealed distinctive, large-scale changes corresponding to successive stages of the disease – reflecting the gradual accumulation of plaques. Obvious defects in microglia function also appeared soon after plaques started to build up. Microscopy imaging of the brain tissue showed that although amyloid-β plaques appeared at the same time, they looked different in each mouse strain. In one, plaques were more compact, while in the other, plaques appeared ‘fluffier’, like cotton wool. In mice with more compacted plaques, microglia recognized the plaques earlier and stopped working sooner, suggesting that plaque structure and microglia defects could be linked. These results shed new light on the role of microglia and their changing protein ‘signals’ during the different stages of Alzheimer’s disease. In the future, this information could help identify people at risk for the disease, so that they can be treated as soon as possible, and to design new therapies to make microglia work again.

背景与目标： 小胶质细胞功能障碍是阿尔茨海默病（AD）的关键病理特征，但对AD过程中小胶质细胞全蛋白组变化及其功能后果知之甚少。在这里，我们在淀粉样蛋白β（Aβ）病理的两种小鼠模型，过表达APPPS1和敲入APP-NL-G-F（APP-KI）模型中对小胶质细胞进行了深入且时间分辨的蛋白质组学表征。我们确定了一大批小胶质细胞Aβ反应蛋白（MARPs），它们反映了Aβ沉积的早期，中期和晚期阶段小胶质细胞改变的异质性，并且较早出现在APPPS1小鼠中。惊人的是，蛋白质组学特征的动力学差异与原纤维Aβ的存在有关，而不是与营养不良的神经突相关，这表明原纤维Aβ可能触发了AD相关的小胶质细胞表型和观察到的功能下降。鉴定出的AD小胶质蛋白质组学指纹为新型分子靶标的功能研究和监测AD进展或治疗效果的潜在生物标记物提供了宝贵的资源。
：阿尔茨海默氏病是一种进行性，不可逆的脑部疾病。老年痴呆症患者的记忆力和其他心理技能存在问题，这会导致更严重的认知能力下降，并最终导致过早死亡。这是由于随着时间的流逝，大脑中越来越多的神经细胞死亡。阿尔茨海默氏症的一个显着特征是称为淀粉样蛋白-β的蛋白质异常高的积累，该蛋白质在大脑中形成了独特的团块，称为“斑块”。大脑具有一种称为小胶质细胞的细胞，可以识别感染，有毒物质和受损细胞，并通过清除它们来防止这些细胞积聚。然而，在阿尔茨海默氏病中，小胶质细胞不能正常工作，这被认为是导致淀粉样β斑块积聚的原因。这意味着在对小胶质细胞活动重要的基因中具有突变的人患此病的风险也较高。尽管小胶质细胞的问题在阿尔茨海默氏病中起着重要作用，但研究人员仍不完全了解为什么小胶质细胞首先会停止工作。还不确切知道小胶质细胞何时以及如何随着阿尔茨海默氏病的进展而改变。为了揭开这个谜团，塞巴斯蒂安·莫纳索尔（Sebastian Monasor），穆勒（Müller）等人。在阿尔茨海默氏病的每个关键阶段对小胶质细胞的分子“指纹”进行了详细研究。实验使用了来自两种不同基因改造小鼠品系的小胶质细胞，它们都以相似的速率发展出了阿尔茨海默氏病的标志，包括淀粉样β斑。对两种菌株的小胶质细胞中蛋白质的分析显示，与疾病的连续阶段相对应的独特，大规模变化-反映了斑块的逐渐积累。斑块开始堆积后不久，小胶质细胞功能也明显出现缺陷。脑组织的显微成像显示，尽管淀粉样蛋白-β噬菌斑同时出现，但在每个小鼠品系中它们看起来都不同。一种是斑块更致密，而另一种则斑块看起来像棉绒一样“蓬松”。在具有更紧密的斑块的小鼠中，小胶质细胞更早地识别了斑块，并且更快地停止工作，这表明斑块结构和小胶质细胞缺陷可以联系在一起。这些结果揭示了小胶质细胞及其在阿尔茨海默氏病不同阶段中不断变化的蛋白质“信号”的作用。将来，这些信息可以帮助识别有患这种疾病风险的人，以便尽快对其进行治疗，并设计新的疗法来使小胶质细胞再次发挥作用。

BACKGROUND & AIMS: OBJECTIVE:To develop a radiographic score for assessment of hand osteoarthritis (OA) that is based on histopathological alterations of the distal (DIP) and proximal (PIP) interphalangeal joints. METHODS:DIP and PIP joints were obtained from corpses (n=40). Plain radiographies of these joints were taken. Joint samples were prepared for histological analysis; cartilage damage was graded according to the Mankin scoring system. A 2×2 Fisher's exact test was applied to define those radiographic features most likely to be associated with histological alterations. Receiver operating characteristic curves were analysed to determine radiographic thresholds. Intraclass correlation coefficients (ICC) estimated intra- and inter-reader variability. Spearman's correlation was applied to examine the relationship between our score and histopathological changes. Differences between groups were determined by a Student's t test. RESULTS:The Interphalangeal Osteoarthritis Radiographic Simplified (iOARS) score is presented. The score is based on histopathological changes of DIP and PIP joints and follows a simple dichotomy whether OA is present or not. The iOARS score relies on three equally ranked radiographic features (osteophytes, joint space narrowing and subchondral sclerosis). For both DIP and PIP joints, the presence of one x-ray features reflects interphalangeal OA. Sensitivity and specificity for DIP joints were 92.3% and 90.9%, respectively, and 75% and 100% for PIP joints. All readers were able to reproduce their own readings in DIP and PIP joints after 4 weeks. The overall agreement between the three readers was good; ICCs ranged from 0.945 to 0.586. Additionally, outcomes of the iOARS score in a hand OA cohort revealed a higher prevalence of interphalangeal joint OA compared with the Kellgren and Lawrence score. CONCLUSIONS:The iOARS score is uniquely based on histopathological alterations of the interphalangeal joints in order to reliably determine OA of the DIP and PIP joints radiographically. Its high specificity and sensitivity together with the dichotomous approach renders the iOARS score reliable, fast to perform and easy to apply. This tool may not only be valuable in daily clinical practice but also in clinical and epidemiological trials.

背景与目标： 目的：基于远端指间关节（DIP）和近端指间关节（PIP）的组织病理学改变，开发放射影像学评分以评估手部骨关节炎（OA）。
方法：DIP和PIP关节取自尸体（n = 40）。拍摄了这些关节的平片。准备关节样本用于组织学分析；软骨损伤根据Mankin评分系统进行分级。应用2×2 Fisher精确检验来定义最可能与组织学改变有关的射线照相特征。分析接收器的工作特性曲线以确定射线照相阈值。类内相关系数（ICC）估计阅读器内和阅读器间的变异性。 Spearman的相关性用于检验我们的评分与组织病理学变化之间的关系。组之间的差异由学生t检验确定。
结果：提出了指间骨关节炎放射照相简化（iOARS）评分。评分基于DIP和PIP关节的组织病理学变化，并遵循简单的二分法，不管是否存在OA。 iOARS评分取决于三个同等的影像学特征（骨赘，关节间隙变窄和软骨下硬化）。对于DIP和PIP关节，一个X射线特征的存在反映了指间OA。 DIP关节的敏感性和特异性分别为92.3％和90.9％，PIP关节的敏感性和特异性分别为75％和100％。 4周后，所有读者都可以在DIP和PIP关节中复制自己的读数。三位读者之间的总体协议是好的。 ICC范围从0.945到0.586。此外，手部OA队列中iOARS评分的结果显示，与Kellgren和Lawrence评分相比，指间关节OA的患病率更高。
结论：iOARS评分独特地基于指间关节的组织病理学改变，以便通过射线照相可靠地确定DIP和PIP关节的OA。它的高特异性和敏感性以及二分法使iOARS评分可靠，快速执行且易于应用。该工具不仅在日常临床实践中有价值，而且在临床和流行病学试验中也可能有价值。