Massachusetts General Hospital/Harvard Medical School, Charlestown, Massachusetts 02129.
Massachusetts General Hospital/Harvard Medical School, Charlestown, Massachusetts 02129
J Neurosci. 2023 Jun 28;43(26):4926-4940. doi: 10.1523/JNEUROSCI.1988-22.2023. Epub 2023 May 26.
The key pathologic entities driving the destruction of synaptic function and integrity during the evolution of Alzheimer's disease (AD) remain elusive. Astrocytes are structurally and functionally integrated within synaptic and vascular circuitry and use calcium-based physiology to modulate basal synaptic transmission, vascular dynamics, and neurovascular coupling, which are central to AD pathogenesis. We used high-resolution multiphoton imaging to quantify all endogenous calcium signaling arising spontaneously throughout astrocytic somata, primary processes, fine processes, and capillary endfeet in the brain of awake APP/PS1 transgenic mice (11 male and 6 female mice). Endogenous calcium signaling within capillary endfeet, while surprisingly as active as astrocytic fine processes, was reduced ∼50% in the brain of awake APP/PS1 mice. Cortical astrocytes, in the presence of amyloid plaques in awake APP/PS1 mice, had a cell-wide increase in intracellular calcium associated with an increased frequency, amplitude, and duration of spontaneous calcium signaling. The cell-wide astrocytic calcium dysregulation was not directly related to distance to amyloid plaques. We could re-create the cell-wide intracellular calcium dysregulation in the absence of amyloid plaques following acute exposure to neuronally derived soluble Abeta from Tg2576 transgenic mice, in the living brain of male C57/Bl6 mice. Our findings highlight a role for astrocytic calcium pathophysiology in soluble-Abeta mediated neurodegenerative processes in AD. Additionally, therapeutic strategies aiming to protect astrocytic calcium physiology from soluble Abeta-mediated toxicity may need to pharmacologically enhance calcium signaling within the hypoactive capillary endfeet while reducing the hyperactivity of spontaneous calcium signaling throughout the rest of the astrocyte. Astrocytic calcium signaling is functionally involved in central pathologic processes of Alzheimer's disease. We quantified endogenous calcium signaling arising spontaneously in the brain of awake APP/PS1 mice, as general anesthesia suppressed astrocytic calcium signaling. Cell-wide astrocytic calcium dysregulation was not related to distance to amyloid plaques but mediated in part by neuronally derived soluble Abeta, supporting a role for astrocytes in soluble-Abeta mediated neurodegeneration. Spontaneous calcium signaling is largely compartmentalized and capillary endfeet were as active as fine processes but hypoactive in the presence of amyloid plaques, while the rest of the astrocyte became hyperactive. The cell-wide calcium pathophysiology in astrocytes may require a combination therapeutic strategy for hypoactive endfeet and astrocytic hyperactivity.
在阿尔茨海默病（AD）的发展过程中，导致突触功能和完整性破坏的关键病理实体仍然难以捉摸。星形胶质细胞在突触和血管回路中结构和功能上是整合在一起的，它们利用基于钙的生理学来调节基础突触传递、血管动力学和神经血管偶联，这些都是 AD 发病机制的核心。我们使用高分辨率多光子成像技术来量化清醒 APP/PS1 转基因小鼠（11 只雄性和 6 只雌性）大脑中整个星形胶质体细胞体、初级突起、细突起和毛细血管终末自发产生的所有内源性钙信号。尽管令人惊讶的是，毛细血管终末内的内源性钙信号与星形胶质细胞的细突起一样活跃，但在清醒的 APP/PS1 小鼠的大脑中却减少了约 50%。在清醒的 APP/PS1 小鼠中，与淀粉样斑块共存的皮质星形胶质细胞的细胞内钙增加，与自发钙信号的频率、幅度和持续时间增加有关。这种全细胞星形胶质细胞钙失调与距淀粉样斑块的距离没有直接关系。我们可以在雄性 C57/Bl6 小鼠活体大脑中，在急性暴露于源自 Tg2576 转基因小鼠的神经元衍生可溶性 Abeta 后，在没有淀粉样斑块的情况下重现全细胞内钙失调。我们的发现强调了星形胶质细胞钙病理生理学在可溶性 Abeta 介导的 AD 神经退行性过程中的作用。此外，旨在保护星形胶质细胞钙生理学免受可溶性 Abeta 介导的毒性的治疗策略可能需要在药理学上增强低活性毛细血管终末内的钙信号，同时降低整个星形胶质细胞中自发钙信号的过度活性。星形胶质细胞钙信号参与了阿尔茨海默病的中枢病理过程。我们在清醒的 APP/PS1 小鼠大脑中自发产生的内源性钙信号进行了定量，因为全身麻醉抑制了星形胶质细胞钙信号。全细胞星形胶质细胞钙失调与距淀粉样斑块的距离无关，但部分由神经元衍生的可溶性 Abeta 介导，支持星形胶质细胞在可溶性 Abeta 介导的神经退行性变中的作用。自发钙信号主要是隔室化的，毛细血管终末与细突起一样活跃，但在淀粉样斑块存在的情况下活性较低，而星形胶质细胞的其余部分变得过度活跃。星形胶质细胞的全细胞钙病理生理学可能需要针对低活性终末和星形胶质细胞过度活跃的联合治疗策略。
