Soluble phospho-tau from Alzheimer's disease hippocampus drives microglial degeneration.
Soluble phospho-tau from Alzheimer's disease hippocampus drives microglial degeneration.
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DOI：
10.1007/s00401-016-1630-5
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发表时间：
2016-12
影响因子：
12.7
通讯作者：
Vitorica J
中科院分区：
文献类型：
--
作者：
Sanchez-Mejias E;Navarro V;Jimenez S;Sanchez-Mico M;Sanchez-Varo R;Nuñez-Diaz C;Trujillo-Estrada L;Davila JC;Vizuete M;Gutierrez A;Vitorica J
小胶质细胞在阿尔茨海默病（AD）发生和发展中的作用尚未阐明。在这里，我们证明了存在一个弱的小胶质细胞的反应，在人类AD海马体，这是在APP为基础的模型中观察到的大规模的小胶质细胞活化。最重要的是，小胶质细胞显示出显著的退行性特征（齿状回> CA 3> CA 1>海马旁回），包括具有球状体的片段化和营养不良过程、减少的数字密度和监视区域（“小胶质结构域”）的显著减少。因此，小胶质细胞覆盖的区域大幅下降，这可能会损害免疫保护，从而影响神经元的存活。体外实验表明，可溶性组分（细胞外/胞质）从AD campi的小胶质细胞是有毒的。这种毒性被AT 8和/或AT 100免疫耗竭消除，证实可溶性磷酸化tau是毒性剂。使用来自磷酸化tau阳性Thy-tau 22激酶的可溶性级分再现这些结果。在吞噬表达可溶性胞内磷酸化tau的SH-SY 5 Y细胞后，培养的小胶质细胞不能存活。由于吞噬能力的小胶质细胞是高度诱导受影响的神经元的凋亡信号，我们推测，积累的神经元内可溶性磷酸化tau蛋白可能会引发小胶质细胞变性的AD海马。AD病理学中的这种小胶质细胞脆弱性为疾病进展的免疫学机制提供了新的见解，并强调了改进或开发新动物模型的必要性，因为目前的模型不能模拟AD患者海马中观察到的小胶质细胞病理学。本文的在线版本（doi：10.1007/s 00401 -016-1630-5）包含补充材料，可供授权用户使用。
The role of microglial cells in the development and progression of Alzheimer’s disease (AD) has not been elucidated. Here, we demonstrated the existence of a weak microglial response in human AD hippocampus which is in contrast to the massive microglial activation observed in APP-based models. Most importantly, microglial cells displayed a prominent degenerative profile (dentate gyrus > CA3 > CA1 > parahippocampal gyrus), including fragmented and dystrophic processes with spheroids, a reduced numerical density, and a significant decrease in the area of surveillance (“microglial domain”). Consequently, there was a substantial decline in the area covered by microglia which may compromise immune protection and, therefore, neuronal survival. In vitro experiments demonstrated that soluble fractions (extracellular/cytosolic) from AD hippocampi were toxic for microglial cells. This toxicity was abolished by AT8 and/or AT100 immunodepletion, validating that soluble phospho-tau was the toxic agent. These results were reproduced using soluble fractions from phospho-tau-positive Thy-tau22 hippocampi. Cultured microglial cells were not viable following phagocytosis of SH-SY5Y cells expressing soluble intracellular phospho-tau. Because the phagocytic capacity of microglial cells is highly induced by apoptotic signals in the affected neurons, we postulate that accumulation of intraneuronal soluble phospho-tau might trigger microglial degeneration in the AD hippocampus. This microglial vulnerability in AD pathology provides new insights into the immunological mechanisms underlying the disease progression and highlights the need to improve or develop new animal models, as the current models do not mimic the microglial pathology observed in the hippocampus of AD patients. The online version of this article (doi:10.1007/s00401-016-1630-5) contains supplementary material, which is available to authorized users.
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DOI：
10.1056/nejmoa1211851
发表时间：
2013-01-10
期刊：
The New England journal of medicine
影响因子：
--
作者：
Guerreiro R;Wojtas A;Bras J;Carrasquillo M;Rogaeva E;Majounie E;Cruchaga C;Sassi C;Kauwe JS;Younkin S;Hazrati L;Collinge J;Pocock J;Lashley T;Williams J;Lambert JC;Amouyel P;Goate A;Rademakers R;Morgan K;Powell J;St George-Hyslop P;Singleton A;Hardy J;Alzheimer Genetic Analysis Group
通讯作者：
Alzheimer Genetic Analysis Group
DOI：
10.1177/1073858414530512
发表时间：
2015-04
期刊：
The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry
影响因子：
--
作者：
Gomez-Nicola D;Perry VH
通讯作者：
Perry VH
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：
5.3
作者：
Jimenez, Sebastian;Baglietto-Vargas, David;Vitorica, Javier
通讯作者：
Vitorica, Javier
影响因子：
14.5
作者：
Hamelin, Lorraine;Lagarde, Julien;Sarazin, Marie
通讯作者：
Sarazin, Marie