Fibrillar Amyloid Plaque Formation Precedes Microglial Activation

In Alzheimer’s disease (AD), hallmark β-amyloid deposits are characterized by the presence of activated microglia around them. Despite an extensive characterization of the relation of amyloid plaques with microglia, little is known about the initiation of this interaction. In this study, the detailed investigation of very small plaques in brain slices in AD transgenic mice of the line APP-PS1(dE9) revealed different levels of microglia recruitment. Analysing plaques with a diameter of up to 10 μm we find that only the half are associated with clear morphologically activated microglia. Utilizing in vivo imaging of new appearing amyloid plaques in double-transgenic APP-PS1(dE9)xCX3CR1+/- mice further characterized the dynamic of morphological microglia activation. We observed no correlation of morphological microglia activation and plaque volume or plaque lifetime. Taken together, our results demonstrate a very prominent variation in size as well as in lifetime of new plaques relative to the state of microglia reaction. These observations might question the existing view that amyloid deposits by themselves are sufficient to attract and activate microglia in vivo.

阿尔茨海默病（Alzheimer’s disease, AD）的标志性病理特征为β-淀粉样蛋白（β-amyloid）沉积，其周围常伴随活化的小胶质细胞（microglia）。尽管学界已对淀粉样斑块与小胶质细胞的关联开展了广泛的表征研究，但二者相互作用的启动机制仍鲜为人知。本研究针对APP-PS1(dE9)系阿尔茨海默病转基因小鼠的脑切片中的极小斑块展开细致分析，发现小胶质细胞的募集水平存在显著差异。对直径不超过10 μm的斑块进行分析后发现，仅半数斑块与形态学明确的活化小胶质细胞存在关联。利用双转基因APP-PS1(dE9)xCX3CR1+/-小鼠的活体成像技术，对体内新发淀粉样斑块的小胶质细胞活化动态进行了进一步表征。研究观察到，小胶质细胞的形态学活化与斑块体积或斑块寿命并无相关性。综上，本研究结果表明，新发斑块的大小及寿命随小胶质细胞的反应状态存在显著差异。上述发现或对“淀粉样沉积本身足以在体内吸引并活化小胶质细胞”这一现有观点提出质疑。