Condello Carlo, Yuan Peng, Schain Aaron, Grutzendler Jaime
Department of Neurology, Yale University, New Haven, Connecticut 06511, USA.
1] Department of Neurology, Yale University, New Haven, Connecticut 06511, USA [2] Department of Neurobiology, Yale University, New Haven, Connecticut 06510, USA.
Nat Commun. 2015 Jan 29;6:6176. doi: 10.1038/ncomms7176.
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 the formation of protofibrillar Aβ42 hotspots that are associated with more severe axonal dystrophy. In ageing, 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.
在阿尔茨海默病（AD）中，β淀粉样蛋白（Aβ）斑块被小胶质细胞突起紧密包裹，但这种现象的意义尚不清楚。在此我们表明，小胶质细胞构成了一个对斑块组成和毒性有深远影响的屏障。利用AD小鼠模型中的高分辨率共聚焦成像和体内双光子成像，我们证明这个屏障可防止斑块向外扩展，并导致形成具有低Aβ42亲和力的致密斑块微区。未被小胶质细胞覆盖的区域不那么致密，但具有高Aβ42亲和力，导致原纤维状Aβ42热点的形成，这些热点与更严重的轴突营养不良有关。在衰老过程中，小胶质细胞覆盖率降低，导致原纤维状Aβ42热点扩大和更严重的神经突营养不良。CX3CR1基因缺失或抗Aβ免疫疗法会导致小胶质细胞覆盖率增加，并减少神经突营养不良。小胶质细胞屏障的失效和神经毒性原纤维状Aβ热点的积累可能构成AD新的治疗和临床成像靶点。
