Astrocytes are important mediators of Aβ-induced neurotoxicity and tau phosphorylation in primary culture.
Astrocytes are important mediators of Aβ-induced neurotoxicity and tau phosphorylation in primary culture.
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星形胶质细胞是Aβ诱导的神经毒性和TAU磷酸化的重要介体。
DOI：
10.1038/cddis.2011.50
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发表时间：
2011-06-02
影响因子：
9
通讯作者：
中科院分区：
文献类型：
--
作者：
阿尔茨海默病（Alzheimer's disease，AD）的病理特征是老年斑中β-淀粉样蛋白（β-amyloid，Aβ）的年龄依赖性沉积、神经元内tau蛋白的积聚（如神经元缠结）、突触功能障碍和神经元死亡。以活化的小胶质细胞和反应性星形胶质细胞的积累为代表的神经炎症被认为调节AD的发展和/或进展。我们使用原代大鼠神经元、星形胶质细胞和混合皮质培养物来研究星形胶质细胞介导的炎症反应在Aβ诱导的神经元损失中的作用。我们报道了少量星形胶质细胞的存在加剧了Aβ诱导的神经元死亡、caspase-3激活和caspase-3切割的tau蛋白的产生。此外，我们发现星形胶质细胞对于在原代神经元中观察到的Aβ诱导的tau蛋白磷酸化是必不可少的。可溶性炎性因子从星形胶质细胞的释放伴随这些事件，并且用抗炎剂米诺环素抑制星形胶质细胞活化减少星形胶质细胞炎性反应和相关的神经元损失。当用米诺环素减弱星形胶质细胞反应时，Aβ诱导的caspase-3活化增加和神经元中caspase-3截短的tau种类的产生减少。总之，这些结果表明，星形胶质细胞是AD模型中Aβ升高下游神经毒性事件的重要介质，并表明促炎细胞因子释放的潜在机制可能是治疗的重要靶点。
Alzheimer's disease (AD) is pathologically characterised by the age-dependent deposition of β-amyloid (Aβ) in senile plaques, intraneuronal accumulation of tau as neurofibrillary tangles, synaptic dysfunction and neuronal death. Neuroinflammation, typified by the accumulation of activated microglia and reactive astrocytes, is believed to modulate the development and/or progression of AD. We have used primary rat neuronal, astrocytic and mixed cortical cultures to investigate the contribution of astrocyte-mediated inflammatory responses during Aβ-induced neuronal loss. We report that the presence of small numbers of astrocytes exacerbate Aβ-induced neuronal death, caspase-3 activation and the production of caspase-3-cleaved tau. Furthermore, we show that astrocytes are essential for the Aβ-induced tau phosphorylation observed in primary neurons. The release of soluble inflammatory factor(s) from astrocytes accompanies these events, and inhibition of astrocyte activation with the anti-inflammatory agent, minocycline, reduces astrocytic inflammatory responses and the associated neuronal loss. Aβ-induced increases in caspase-3 activation and the production of caspase-3-truncated tau species in neurons were reduced when the astrocytic response was attenuated with minocycline. Taken together, these results show that astrocytes are important mediators of the neurotoxic events downstream of elevated Aβ in models of AD, and suggest that mechanisms underlying pro-inflammatory cytokine release might be an important target for therapy.
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影响因子：
5.3
作者：
Hickman, Suzanne E.;Allison, Elizabeth K.;El Khoury, Joseph
通讯作者：
El Khoury, Joseph
影响因子：
16.2
作者：
Bhaskar, Kiran;Konerth, Megan;Kokiko-Cochran, Olga N.;Cardona, Astrid;Ransohoff, Richard M.;Lamb, Bruce T.
通讯作者：
Lamb, Bruce T.
DOI：
10.1523/jneurosci.1243-10.2010
发表时间：
2010-09-22
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Jana A;Pahan K
通讯作者：
Pahan K
DOI：
10.3233/jad-2010-100204
发表时间：
2010
期刊：
Journal of Alzheimer's disease : JAD
影响因子：
--
作者：
Parachikova A;Vasilevko V;Cribbs DH;LaFerla FM;Green KN
通讯作者：
Green KN
DOI：
10.1083/jcb.100.2.384
发表时间：
1985-02
期刊：
The Journal of cell biology
影响因子：
--
作者：
Hatten ME
通讯作者：
Hatten ME