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首页> 外文会议>Society of Photo-Optical Instrumentation Engineers;SPIE Medical Imaging Conference >3D profiling of amyloid plaque-associated microglia and neuronal damage on confocal uorescence images to aid drug discovery in Alzheimer's Disease
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3D profiling of amyloid plaque-associated microglia and neuronal damage on confocal uorescence images to aid drug discovery in Alzheimer's Disease

机译：淀粉样斑块相关小胶质细胞的3D分析和共聚焦神经元损伤荧光图像有助于阿尔茨海默氏病的药物发现

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Alzheimer's disease (AD), one of the most common cause of dementia, is a complex neurodegenerative diseasemarked by amyloid-β (Aβ) plaques and hyperphosphorylated tau tangles. Genome-wide association studies haveidentied rare variants of genes that implicate novel biological underpinnings of AD, unearthing untapped in-sights into modulation of innate immune pathways. Recent studies have implicated crucial functions of microglia(brain's resident immune cells) clustering around Aβ plaques, such as plaque compaction and containment, sug-gesting a beneficial impact on limiting the extent of neuronal damage. In order to test this hypothesis, extractionof neuronal damage characteristics in correlation with microglia coverage is required on a single plaque level. Weutilized immunohistochemistry and confocal microscopy to collect 3D image data sets from an AD mouse model.For the quantitative correlative assessment of the heterogeneity of microglia clustering and plaque-associatedneuronal damage, we developed a multi-step image analysis pipeline consisting of (a) U-Net based automatedregion of interest (ROI) detection algorithm (96 % true positive rate), (b) FIJI-based custom-built image pro-filing tool that creates biologically meaningful image features from ROIs (plaques), and © Spotfire-based datavisualization dashboard. Our proof-of-concept data set shows that plaque-associated microglia clustering corre-lates with lower neuronal damage in a disease stage and plaque size-dependent manner. This novel platform hasvalidated our working hypothesis on protective functions of microglia during AD pathology. Future applicationsof the plaque profiling pipeline will enable unbiased quantitative assessment of potential neuroprotective effectsby pharmacological or genetic interventions in preclinical AD models with amyloid pathology.
机译：阿尔茨海默氏病（AD）是痴呆症最常见的原因之一，是一种复杂的神经退行性疾病 以淀粉样蛋白-β（Aβ）斑块和磷酸化的tau缠结为特征。全基因组关联研究 鉴定出的罕见变体，这些基因暗示了AD的新生物基础，未发掘且未发掘的 注意到先天免疫途径的调节。最近的研究暗示小胶质细胞的关键功能 （大脑的固有免疫细胞）聚集在Aβ斑块周围，例如斑块压实和遏制，提示- 对限制神经元损害的程度产生有益的影响。为了检验这个假设，提取 在单个斑块水平上，需要与小胶质细胞覆盖相关的神经元损伤特征。我们 利用免疫组化和共聚焦显微镜从AD小鼠模型中收集3D图像数据集。 用于小胶质细胞聚集和斑块相关异质性的定量相关评估 神经元损伤，我们开发了一个多步骤的图像分析管道，其中包括（a）基于U-Net的自动化 感兴趣区域（ROI）检测算法（96％真实阳性率），（b）基于FIJI的定制图像pro- 归档工具，可从ROI（斑块）和基于©Spotfire的数据中创建具有生物学意义的图像特征 可视化仪表板。我们的概念验证数据集显示，与斑块相关的小胶质细胞簇相关 在疾病阶段和斑块大小相关的方式下，神经元损伤程度较低。这个新颖的平台具有 验证了我们关于AD病理过程中小胶质细胞保护功能的假设。未来的应用 斑块分析管线的分析将能够对潜在的神经保护作用进行公正的定量评估 在具有淀粉样蛋白病理学的临床前AD模型中进行药理或遗传干预。

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