背景:小胶质细胞激活是阿尔茨海默病(AD)神经病理学的一个标志,但对小胶质细胞在脑中的区域相互作用的影响知之甚少。我们假设小胶质细胞的激活在健康的大脑中是区域同步的,但与正在进行的神经退行性疾病经历区域不同步。我们解决了小胶质细胞连接体的存在,并研究了小胶质细胞去同步化作为AD生物标志物。
方法:为了验证概念,我们在小鼠中进行了小胶质细胞清除,以测试当清除小胶质细胞时,18kDa转运蛋白(TSPO)-PET的区域间相关系数(ICCs)是否发生变化.接下来,我们评估了功能失调的小胶质细胞和AD病理生理学对小鼠脑中TSPO-PETICC的影响,然后翻译为人类AD连续体数据集。我们将个性化的小胶质细胞去同步指数与认知表现相关联。最后,我们在小鼠中进行了单细胞放射性赛车(scradiotracing),以确保测量的去同步化的小胶质细胞来源.
结果:小胶质细胞耗尽的小鼠在所有脑室中显示出强ICC减少,表明小胶质细胞特异性去同步化。AD小鼠模型显示小胶质细胞同步性显著降低,与病理改变的脑区细胞放射性示踪剂摄取的变异性增加有关。AD连续体中的人类表明与认知下降相关的小胶质细胞同步性的阶段依赖性降低。小鼠的scRadiotracing表明,TSPO信号的增加归因于小胶质细胞。
结论:在淀粉样蛋白模型中使用TSPO-PET成像对小胶质细胞耗尽和放射性生长的小鼠进行成像,我们提供了可以在小鼠大脑中评估小胶质细胞连接组的第一个证据。小胶质细胞同步性与AD的认知功能下降密切相关,可以作为疾病进展的独立个性化生物标志物。
BACKGROUND: Microglial activation is one hallmark of Alzheimer disease (AD) neuropathology but the impact of the regional interplay of microglia cells in the brain is poorly understood. We hypothesized that microglial activation is regionally synchronized in the healthy brain but experiences regional desynchronization with ongoing neurodegenerative disease. We addressed the existence of a microglia connectome and investigated microglial desynchronization as an AD biomarker.
METHODS: To validate the concept, we performed microglia depletion in mice to test whether interregional correlation coefficients (ICCs) of 18 kDa translocator protein (
TSPO)-PET change when microglia are cleared. Next, we evaluated the influence of dysfunctional microglia and AD pathophysiology on
TSPO-PET ICCs in the mouse brain, followed by translation to a human AD-continuum dataset. We correlated a personalized microglia desynchronization index with cognitive performance. Finally, we performed single-cell radiotracing (scRadiotracing) in mice to ensure the microglial source of the measured desynchronization.
RESULTS: Microglia-depleted mice showed a strong ICC reduction in all brain compartments, indicating microglia-specific desynchronization. AD mouse models demonstrated significant reductions of microglial synchronicity, associated with increasing variability of cellular radiotracer uptake in pathologically altered brain regions. Humans within the AD-continuum indicated a stage-depended reduction of microglia synchronicity associated with cognitive decline. scRadiotracing in mice showed that the increased
TSPO signal was attributed to microglia.
CONCLUSIONS: Using
TSPO-PET imaging of mice with depleted microglia and scRadiotracing in an amyloid model, we provide first evidence that a microglia connectome can be assessed in the mouse brain. Microglia synchronicity is closely associated with cognitive decline in AD and could serve as an independent personalized biomarker for disease progression.