Nakata Kaito, Sakamoto Joe, Otomo Kohei, Sato Masanao, Ishii Hirokazu, Tsutsumi Motosuke, Enoki Ryosuke, Nemoto Tomomi
School of Life Science, The Graduate University for Advanced Studies, SOKENDAI, Okazaki, Japan.
Division of Biophotonics, National Institute for Physiological Sciences (NIPS), National Institutes of Natural Sciences (NINS), Okazaki, Japan.
Sci Rep. 2025 May 29;15(1):18944. doi: 10.1038/s41598-025-03931-7.
Alzheimer's disease (AD) is a progressive neurodegenerative disorder that causes cognitive decline. Uncovering the mechanisms of neurodegeneration in the early stages is essential to establish a treatment for AD. Recent research has proposed the hypothesis that amyloid-β (Aβ) oligomers elicit an excessive glutamate release from astrocytes toward synapses through intracellular free Ca ([Ca]) elevations in astrocytes, finally resulting in neuronal dendritic spine loss. Under physiological conditions, astrocytic [Ca] elevations range spatially from microdomains to network-wide propagation and temporally from milliseconds to tens of seconds. Astrocytic localized and fast [Ca] elevations might correlate with glutamate release; however, the Aβ-induced alteration of localized, fast astrocytic [Ca] elevations remains unexplored. In this study, we quantitatively investigated the Aβ dimers-induced changes in the spatial and temporal patterns of [Ca] in a primary culture of astrocytes by two-photon excitation spinning-disk confocal microscopy. The frequency of fast [Ca] elevations occurring locally in astrocytes (≤ 0.5 s, ≤ 35 µm) and [Ca] event occupancy relative to cell area significantly increased after exposure to Aβ dimers. The effect of Aβ dimers appeared above 500 nM, and these Aβ dimers-induced [Ca] elevations were primarily mediated by a metabotropic purinergic receptor (P2Y1 receptor) and Ca release from the endoplasmic reticulum. Our findings suggest that the Aβ dimers-induced alterations and hyperactivation of astrocytic [Ca] is a candidate cellular mechanism in the early stages of AD.
阿尔茨海默病（AD）是一种导致认知功能衰退的进行性神经退行性疾病。揭示早期神经退行性变的机制对于建立AD的治疗方法至关重要。最近的研究提出了一种假说，即淀粉样β（Aβ）寡聚体通过星形胶质细胞内游离钙（[Ca]）升高，引发星形胶质细胞向突触过度释放谷氨酸，最终导致神经元树突棘丢失。在生理条件下，星形胶质细胞[Ca]升高在空间上从微区到全网络传播，在时间上从毫秒到数十秒。星形胶质细胞局部和快速的[Ca]升高可能与谷氨酸释放相关；然而，Aβ诱导的星形胶质细胞局部、快速[Ca]升高的改变仍未得到探索。在本研究中，我们通过双光子激发旋转盘共聚焦显微镜定量研究了Aβ二聚体诱导的原代星形胶质细胞培养物中[Ca]的时空模式变化。暴露于Aβ二聚体后，星形胶质细胞局部快速[Ca]升高（≤0.5秒，≤35微米）的频率以及相对于细胞面积的[Ca]事件占有率显著增加。Aβ二聚体的作用在500 nM以上出现，这些Aβ二聚体诱导的[Ca]升高主要由代谢型嘌呤能受体（P2Y1受体）和内质网释放的钙介导。我们的研究结果表明，Aβ二聚体诱导的星形胶质细胞[Ca]改变和过度激活是AD早期阶段的一种潜在细胞机制。
