Department of Translational Neuroscience, University Medical Center Utrecht Brain Center, Utrecht University, Utrecht, The Netherlands.
Swammerdam Institute for Life Sciences, Center for Neuroscience, Cellular and Computational Neuroscience, University of Amsterdam, Amsterdam, The Netherlands.
J Neurosci Res. 2022 Jun;100(6):1281-1295. doi: 10.1002/jnr.25042. Epub 2022 Mar 16.
Astrocytes are critical for healthy brain function. In Alzheimer's disease, astrocytes become reactive, which affects their signaling properties. Here, we measured spontaneous calcium transients ex vivo in hippocampal astrocytes in brain slices containing the dentate gyrus of 6- (6M) and 9-month-old (9M) APPswe/PSEN1dE9 (APP/PS1) mice. We investigated the frequency and duration of calcium transients in relation to aging, amyloid-β (Aβ) pathology, and the proximity of the astrocyte to Aβ plaques. The 6M APP/PS1 astrocytes showed no change in spontaneous calcium-transient properties compared to wild-type (WT) astrocytes. 9M APP/PS1 astrocytes, however, showed more hyperactivity compared to WT, characterized by increased spontaneous calcium transients that were longer in duration. Our data also revealed an effect of aging, as 9M astrocytes overall showed an increase in calcium activity compared to 6M astrocytes. Subsequent calcium-wave analysis showed an increase in sequential calcium transients (i.e., calcium waves) in 9M astrocytes, suggesting increased network activity ex vivo. Further analysis using null models revealed that this network effect is caused by chance, due to the increased number of spontaneous transients. Our findings show that alterations in calcium signaling in individual hippocampal astrocytes of APP/PS1 mice are subject to both aging and Aβ pathology but these do not lead to a change in astrocyte network activity. These alterations in calcium dynamics of astrocytes may help to understand changes in neuronal physiology leading to cognitive decline and ultimately dementia.
星形胶质细胞对于大脑的正常功能至关重要。在阿尔茨海默病中,星形胶质细胞变得活跃,从而影响了它们的信号转导特性。在此,我们在含有齿状回的脑切片中测量了 6 月龄(6M)和 9 月龄(9M)APPswe/PSEN1dE9(APP/PS1)小鼠海马星形胶质细胞的自发钙瞬变,并研究了钙瞬变的频率和持续时间与衰老、淀粉样β(Aβ)病理学以及星形胶质细胞与 Aβ斑块的接近程度的关系。与野生型(WT)星形胶质细胞相比,6M APP/PS1 星形胶质细胞的自发钙瞬变特性没有变化。然而,与 WT 相比,9M APP/PS1 星形胶质细胞表现出更多的活动过度,其特征是自发钙瞬变持续时间更长。我们的数据还揭示了衰老的影响,因为与 6M 星形胶质细胞相比,9M 星形胶质细胞的钙活性总体增加。随后的钙波分析显示,9M 星形胶质细胞中连续钙瞬变(即钙波)增加,表明体外网络活动增加。使用空模型的进一步分析表明,这种网络效应是由于自发瞬变数量的增加而偶然发生的。我们的研究结果表明,APP/PS1 小鼠海马星形胶质细胞中钙信号的改变既受到衰老的影响,也受到 Aβ病理学的影响,但这并没有导致星形胶质细胞网络活动的改变。星形胶质细胞钙动力学的这些改变可能有助于理解导致认知能力下降和最终痴呆的神经元生理学变化。