Paasila Patrick Jarmo, Davies Danielle Suzanne, Sutherland Greg Trevor, Goldsbury Claire
Discipline of Pathology, School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, NSW 2006, Australia.
Discipline of Anatomy and Histology, School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, NSW 2006, Australia.
Free Neuropathol. 2020;1:20. doi: 10.17879/freeneuropathology-2020-2845. Epub 2020 Aug 4.
Alzheimer's disease (AD) is a late-onset disease that has proved difficult to model. Microglia are implicated in AD, but reports vary on precisely when and how in the sequence of pathological changes they become involved. Here, post-mortem human tissue from two differentially affected regions of the AD brain and from non-demented individuals with a high load of AD-type pathology (high pathology controls) was used to model the disease time course in order to determine how microglial activation relates temporally to the deposition of hallmark amyloid-β (Aβ) and hyperphosphorylated microtubule associated protein tau pathology. Immunofluorescence against the pan-microglial marker, ionised calcium-binding adapter molecule 1 (IBA1), Aβ and tau, was performed in the primary motor cortex (PMC), a region relatively spared of AD pathological changes, and compared to the severely affected inferior temporal cortex (ITC) in the same cases. Unlike the ITC, the PMC in the AD cases was spared of any degenerative changes in cortical thickness and the density of Betz cells and total neurons. The clustering of activated microglia was greatest in the PMC of AD cases and high pathology controls compared to the ITC. This suggests microglial activation is most prominent in the early phases of AD pathophysiology. Nascent tau inclusions were found in neuritic plaques in the PMC but were more numerous in the ITC of the same case. This shows that tau positive neuritic plaques begin early in AD which is likely of pathogenic importance, however major tau deposition follows the accumulation of Aβ and clustering of activated microglia. Importantly, findings presented here demonstrate that different states of microglial activation, corresponding to regional accumulations of Aβ and tau, are present simultaneously in the same individual; an important factor for consideration if targeting these cells for therapeutic intervention.
阿尔茨海默病（AD）是一种晚发性疾病，已被证明难以进行模型构建。小胶质细胞与AD有关，但关于它们在病理变化序列中具体何时以及如何参与其中的报道各不相同。在这里，使用来自AD大脑两个不同受影响区域以及来自具有高负荷AD型病理（高病理对照组）的非痴呆个体的尸检人体组织来模拟疾病的时间进程，以确定小胶质细胞激活在时间上与标志性淀粉样β蛋白（Aβ）沉积以及微管相关蛋白tau的过度磷酸化病理变化之间的关系。在主要运动皮层（PMC）（一个相对较少发生AD病理变化的区域）中，针对泛小胶质细胞标志物离子化钙结合衔接分子1（IBA1）、Aβ和tau进行了免疫荧光检测，并与同一病例中受严重影响的颞下回（ITC）进行了比较。与ITC不同，AD病例中的PMC在皮质厚度、贝茨细胞密度和总神经元数量方面没有任何退行性变化。与ITC相比，AD病例和高病理对照组的PMC中活化小胶质细胞的聚集最为明显。这表明小胶质细胞激活在AD病理生理学的早期阶段最为突出。在PMC的神经炎性斑块中发现了新生的tau包涵体，但在同一病例的ITC中数量更多。这表明tau阳性神经炎性斑块在AD早期就开始出现，这可能具有致病重要性，然而主要的tau沉积是在Aβ积累和活化小胶质细胞聚集之后发生的。重要的是，这里呈现的研究结果表明，与Aβ和tau的区域积累相对应的不同小胶质细胞激活状态在同一个体中同时存在；如果将这些细胞作为治疗干预的靶点，这是一个需要考虑的重要因素。
