Abedin Md Joynal, Lee Yee Fun, Zhang Melinda, Russ Alyssa N, Gerashchenko Dmitry, Bacskai Brian J, Kastanenka Ksenia V
Massachusetts General Hospital, Harvard Medical School.
Brown University.
Res Sq. 2025 Jun 15:rs.3.rs-6682029. doi: 10.21203/rs.3.rs-6682029/v1.
Alzheimer's disease (AD) is characterized by presence of extracellular amyloid plaques, intracellular tau tangles, and extensive neuronal cell death. In addition to neurons, astrocytes modulate neuronal network activity through tripartite synapses and are increasingly recognized for their involvement in AD pathology. Astrocytic calcium signaling has been implicated in AD pathological processes, including disrupted synaptic transmission, dysregulated glutamate homeostasis, and impaired vascular function via astrocytic endfeet. However, a systematic analysis of calcium dynamics within specific astrocytic compartments has been lacking. Using in vivo multiphoton imaging of Yellow Cameleon 3.6, a genetically encoded calcium indicator targeted to astrocytes in APP/PS1 mice, we analyzed spontaneous calcium transients in cortical astrocytes at 4-6 months of age. We quantified event rate, activity duration, area under the curve (AUC), and peak amplitude across four compartments: soma, processes, microdomains, and endfeet. In APP/PS1 mice, somas exhibited increased activity duration and peak amplitude, while processes and microdomains showed reduced duration, AUC, and amplitude despite higher event rates. Endfeet showed reductions in all parameters. Correlation analysis revealed enhanced astrocyte synchrony in APP/PS1 mice, with distance-dependent correlation decay observed only in nontransgenic controls. Our findings highlight compartment-specific disruptions of astrocytic calcium activity caused by amyloidosis.
阿尔茨海默病（AD）的特征是细胞外淀粉样斑块、细胞内tau缠结的存在以及广泛的神经元细胞死亡。除神经元外，星形胶质细胞通过三方突触调节神经元网络活动，并且其在AD病理过程中的作用越来越受到认可。星形胶质细胞的钙信号传导与AD病理过程有关，包括突触传递中断、谷氨酸稳态失调以及通过星形胶质细胞终足导致的血管功能受损。然而，目前缺乏对特定星形胶质细胞区室钙动力学的系统分析。我们使用针对APP/PS1小鼠星形胶质细胞的基因编码钙指示剂黄变色龙3.6进行体内多光子成像，分析了4至6月龄皮质星形胶质细胞中的自发钙瞬变。我们对四个区室（胞体、突起、微区和终足）的事件发生率、活动持续时间、曲线下面积（AUC）和峰值幅度进行了量化。在APP/PS1小鼠中，胞体的活动持续时间和峰值幅度增加，而突起和微区尽管事件发生率较高，但持续时间、AUC和幅度均降低。终足的所有参数均降低。相关性分析显示APP/PS1小鼠中星形胶质细胞同步性增强，仅在非转基因对照中观察到距离依赖性相关性衰减。我们的研究结果突出了淀粉样变性导致的星形胶质细胞钙活性的区室特异性破坏。
