Microglia constitute a barrier that prevents neurotoxic protofibrillar Aβ42 hotspots around plaques.
Microglia constitute a barrier that prevents neurotoxic protofibrillar Aβ42 hotspots around plaques.
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小胶质细胞构成一个阻止斑块周围神经毒性原纤维Aβ42热点的障碍。
DOI：
10.1038/ncomms7176
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发表时间：
2015-01-29
影响因子：
16.6
通讯作者：
Grutzendler, Jaime
中科院分区：
文献类型：
--
作者：
Condello, Carlo;Yuan, Peng;Schain, Aaron;Grutzendler, Jaime
在阿尔茨海默病（AD）中，β-淀粉样蛋白（Aβ）斑块被小胶质细胞紧密包裹，但这种现象的意义尚不清楚。在这里，我们表明小胶质细胞构成了对斑块组成和毒性有深远影响的屏障。通过在AD小鼠模型中使用高分辨率共聚焦和体内双光子成像，我们证明了这种屏障可以阻止斑块向外扩张，并导致斑块微区紧密，具有低Aβ42亲和力。小胶质细胞覆盖的区域不致密，但具有高Aβ42亲和力，导致原纤维Aβ42热点的形成，这与更严重的轴突营养不良有关。随着年龄的增长，小胶质细胞的覆盖减少，导致原纤维Aβ42热点增大，神经营养不良更加严重。CX3CR1基因缺失或抗a β免疫治疗可导致小胶质细胞覆盖范围的扩大和神经营养不良的减少。小胶质细胞屏障的失效和神经毒性原纤维Aβ热点的积累可能成为阿尔茨海默病新的治疗和临床成像靶点。
In Alzheimer’s disease (AD), β-amyloid (Aβ) plaques are tightly enveloped by microglia processes, but the significance of this phenomenon is unknown. Here we show that microglia constitute a barrier with profound impact on plaque composition and toxicity. Using high-resolution confocal and in vivo two-photon imaging in AD mouse models, we demonstrate that this barrier prevents outward plaque expansion and leads to compact plaque microregions with low Aβ42 affinity. Areas uncovered by microglia are less compact but have high Aβ42 affinity, leading to formation of protofibrillar Aβ42 hotspots that are associated with more severe axonal dystrophy. In aging, microglia coverage is reduced, leading to enlarged protofibrillar Aβ42 hotspots and more severe neuritic dystrophy. CX3CR1 gene deletion or anti-Aβ immunotherapy causes expansion of microglia coverage and reduced neuritic dystrophy. Failure of the microglia barrier and the accumulation of neurotoxic protofibrillar Aβ hotspots may constitute novel therapeutic and clinical imaging targets for AD.
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影响因子：
16.2
作者：
Kim, Jungsu;Basak, Jacob M.;Holtzman, David M.
通讯作者：
Holtzman, David M.
影响因子：
15.1
作者：
Kayed R;Head E;Sarsoza F;Saing T;Cotman CW;Necula M;Margol L;Wu J;Breydo L;Thompson JL;Rasool S;Gurlo T;Butler P;Glabe CG
通讯作者：
Glabe CG
影响因子：
15.1
作者：
Kayed R;Canto I;Breydo L;Rasool S;Lukacsovich T;Wu J;Albay R 3rd;Pensalfini A;Yeung S;Head E;Marsh JL;Glabe C
通讯作者：
Glabe C
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
影响因子：
5.3
作者：
Hickman, Suzanne E.;Allison, Elizabeth K.;El Khoury, Joseph
通讯作者：
El Khoury, Joseph