Genetics and other data modalities indicate that microglia play a critical role in Alzheimer's disease progression, but details of the disease-driving influence of microglia are poorly understood. Microglial cells can be parsed into subtypes based on their histological appearance. One subtype of microglia, termed dystrophic microglia, is characterized structurally by fragmented processes and cytoplasmic decay, and their presence has been associated with ageing and neurodegeneration. Recent studies suggest that the interaction between tau proteins and amyloid-β might induce dystrophic changes in microglia, potentially linking amyloid-β and tau pathologies to their effects on these microglia. We developed a study of human brains to test the hypothesis that dystrophic microglia are involved in Alzheimer's disease progression. We speculated that if their presence is unique to Alzheimer's disease neuropathological change, they would be substantially more common in Alzheimer's disease neuropathological change than in neurodegenerative diseases characterized by other proteinopathies, e.g. α-synuclein or transactive response (TAR) DNA-binding protein 43 kDa (TDP-43) pathology. Our analyses used histologically stained sections from five human brain regions of 64 individuals across six disease states, from healthy controls to advanced Alzheimer's disease stages, including comparative conditions such as Lewy body disease and limbic-predominant age-related TDP-43 encephalopathy neuropathological change. Using stereological sampling and digital pathology, we assessed populations of ramified, hypertrophic and dystrophic microglia. We found a significant increase in dystrophic microglia in areas affected early by Alzheimer's disease neuropathological change, suggesting a disease-specific role in neuropathology. Mediation analysis and structural equation modelling suggest that dystrophic microglia might impact the regional spread of Alzheimer's disease neuropathological change. In the mediation model, tau was found to be the initiating factor leading to the development of dystrophic microglia, which was then associated with the spread of amyloid-β and tau. These results suggest that a loss of the protective role of microglia could contribute to the spread of Alzheimer's disease neuropathological change and indicate that further research into preserving microglial function might be warranted.

中文翻译：

---

探索营养不良性小胶质细胞与阿尔茨海默病神经病理学传播之间的联系


遗传学和其他数据模式表明，小胶质细胞在阿尔茨海默病进展中起着关键作用，但对小胶质细胞的疾病驱动影响的细节知之甚少。小胶质细胞可以根据其组织学外观解析为亚型。小胶质细胞的一种亚型，称为营养不良性小胶质细胞，在结构上以碎片化过程和细胞质衰变为特征，它们的存在与衰老和神经退化有关。最近的研究表明，tau 蛋白和β淀粉样蛋白之间的相互作用可能会诱导小胶质细胞的营养不良变化，从而可能将淀粉样蛋白β和 tau 病理与它们对这些小胶质细胞的影响联系起来。我们开展了一项对人脑的研究，以检验营养不良性小胶质细胞与阿尔茨海默病进展有关的假设。我们推测，如果它们的存在是阿尔茨海默病神经病理学变化所独有的，那么它们在阿尔茨海默病神经病理学变化中将比在其他蛋白质病为特征的神经退行性疾病中更常见，例如 α-突触核蛋白或反式反应 （TAR） DNA 结合蛋白 43 kDa （TDP-43） 病理学。我们的分析使用了来自六种疾病状态的 64 个人的 5 个人脑区域的组织学染色切片，从健康对照到晚期阿尔茨海默病阶段，包括路易体病和边缘综合征为主的年龄相关 TDP-43 脑病神经病理学变化等比较病症。使用立体采样和数字病理学，我们评估了分枝、肥厚和营养不良的小胶质细胞群。 我们发现，在受阿尔茨海默病神经病理学变化影响的早期区域，营养不良的小胶质细胞显着增加，这表明疾病在神经病理学中的作用。中介分析和结构方程模型表明，营养不良性小胶质细胞可能会影响阿尔茨海默病神经病理学变化的区域传播。在中介模型中，发现 tau 是导致营养不良性小胶质细胞发展的起始因素，然后与淀粉样蛋白β和 tau 的扩散有关。这些结果表明，小胶质细胞保护作用的丧失可能导致阿尔茨海默病神经病理变化的传播，并表明可能需要进一步研究保留小胶质细胞功能。