阿尔茨海默病小鼠星形胶质细胞中的同步性过度活跃和细胞间钙波
Synchronous hyperactivity and intercellular calcium waves in astrocytes in Alzheimer mice.
作者信息
Kuchibhotla Kishore V, Lattarulo Carli R, Hyman Bradley T, Bacskai Brian J
机构信息
Massachusetts General Hospital, Department of Neurology/Alzheimer's Disease Research Laboratory, 114 16th Street, Charlestown, MA 02129, USA.
出版信息
Science. 2009 Feb 27;323(5918):1211-5. doi: 10.1126/science.1169096.
Abstract
Although senile plaques focally disrupt neuronal health, the functional response of astrocytes to Alzheimer's disease pathology is unknown. Using multiphoton fluorescence lifetime imaging microscopy in vivo, we quantitatively imaged astrocytic calcium homeostasis in a mouse model of Alzheimer's disease. Resting calcium was globally elevated in the astrocytic network, but was independent of proximity to individual plaques. Time-lapse imaging revealed that calcium transients in astrocytes were more frequent, synchronously coordinated across long distances, and uncoupled from neuronal activity. Furthermore, rare intercellular calcium waves were observed, but only in mice with amyloid-beta plaques, originating near plaques and spreading radially at least 200 micrometers. Thus, although neurotoxicity is observed near amyloid-beta deposits, there exists a more general astrocyte-based network response to focal pathology.
摘要
尽管老年斑会局部破坏神经元健康，但星形胶质细胞对阿尔茨海默病病理的功能反应尚不清楚。我们利用多光子荧光寿命成像显微镜在体内对阿尔茨海默病小鼠模型中的星形胶质细胞钙稳态进行了定量成像。星形胶质细胞网络中的静息钙在整体上有所升高，但与单个斑块的距离无关。延时成像显示，星形胶质细胞中的钙瞬变更为频繁，在长距离上同步协调，并且与神经元活动解耦。此外，还观察到罕见的细胞间钙波，但仅在有β淀粉样蛋白斑块的小鼠中出现，起源于斑块附近并沿径向扩散至少200微米。因此，尽管在β淀粉样蛋白沉积物附近观察到神经毒性，但对局部病理存在更普遍的基于星形胶质细胞的网络反应。
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Neuron. 2008 Sep 25;59(6):932-46. doi: 10.1016/j.neuron.2008.09.004.
2
Clusters of hyperactive neurons near amyloid plaques in a mouse model of Alzheimer's disease.在阿尔茨海默病小鼠模型中，淀粉样斑块附近的高活性神经元簇。
Science. 2008 Sep 19;321(5896):1686-9. doi: 10.1126/science.1162844.
3
Abeta plaques lead to aberrant regulation of calcium homeostasis in vivo resulting in structural and functional disruption of neuronal networks.淀粉样β蛋白斑块导致体内钙稳态的异常调节，从而造成神经网络的结构和功能破坏。
Neuron. 2008 Jul 31;59(2):214-25. doi: 10.1016/j.neuron.2008.06.008.
4
Tuned responses of astrocytes and their influence on hemodynamic signals in the visual cortex.星形胶质细胞的调谐反应及其对视觉皮层血流动力学信号的影响。
Science. 2008 Jun 20;320(5883):1638-43. doi: 10.1126/science.1156120.
5
Loss of IP3 receptor-dependent Ca2+ increases in hippocampal astrocytes does not affect baseline CA1 pyramidal neuron synaptic activity.海马星形胶质细胞中依赖三磷酸肌醇受体的钙离子增加的丧失并不影响基底CA1锥体神经元的突触活动。
J Neurosci. 2008 May 7;28(19):4967-73. doi: 10.1523/JNEUROSCI.5572-07.2008.
6
Rapid appearance and local toxicity of amyloid-beta plaques in a mouse model of Alzheimer's disease.阿尔茨海默病小鼠模型中β-淀粉样蛋白斑块的快速出现及局部毒性
Nature. 2008 Feb 7;451(7179):720-4. doi: 10.1038/nature06616.
7
Two-photon imaging of astrocytic Ca2+ signaling and the microvasculature in experimental mice models of Alzheimer's disease.阿尔茨海默病实验小鼠模型中星形胶质细胞Ca2+信号传导和微血管的双光子成像
Ann N Y Acad Sci. 2007 Feb;1097:40-50. doi: 10.1196/annals.1379.004.
8
Mechanisms of Disease: astrocytes in neurodegenerative disease.疾病机制：神经退行性疾病中的星形胶质细胞
Nat Clin Pract Neurol. 2006 Dec;2(12):679-89. doi: 10.1038/ncpneuro0355.
9
Plaque-derived oxidative stress mediates distorted neurite trajectories in the Alzheimer mouse model.斑块衍生的氧化应激介导阿尔茨海默病小鼠模型中神经突轨迹的扭曲。
J Neuropathol Exp Neurol. 2006 Nov;65(11):1082-9. doi: 10.1097/01.jnen.0000240468.12543.af.
10
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