Fibrinogen Induces Microglia-Mediated Spine Elimination and Cognitive Impairment in an Alzheimer's Disease Model
Fibrinogen Induces Microglia-Mediated Spine Elimination and Cognitive Impairment in an Alzheimer's Disease Model
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DOI：
10.1016/j.neuron.2019.01.014
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发表时间：
2019-03-20
期刊：
影响因子：
16.2
通讯作者：
Akassoglou, Katerina
中科院分区：
文献类型：
--
作者：
Merlini, Mario;Rafalski, Victoria A.;Akassoglou, Katerina
脑血管改变是阿尔茨海默病(AD)发病机制的一个重要特征。然而，血管损伤是否会导致突触功能障碍，以及它如何与淀粉样蛋白病理协同作用，导致神经炎症和认知功能下降，目前仍知之甚少。在这里，我们表明，血液蛋白纤维蛋白原诱导脊柱消除和促进认知障碍介导的CD11b-CD18小胶质细胞激活。3D分子标记结合体内重复的双光子成像，在清除的小鼠和人类AD脑中显示，局灶性纤维蛋白原沉积与树突棘的丢失独立于淀粉样斑块有关。通过抑制活性氧物种(ROS)的产生或CD11b的遗传消融来防止纤维蛋白原诱导的脊柱消除。在5XFAD小鼠模型中，CD11b的纤维蛋白原结合基序的遗传消除减少了神经炎症、突触缺陷和认知能力下降。因此，纤维蛋白原通过CD11b诱导的脊椎消除和认知功能下降将脑血管损伤与免疫介导的神经变性联系在一起，可能在AD及相关疾病中具有重要意义。
Cerebrovascular alterations are a key feature of Alzheimer's disease (AD) pathogenesis. However, whether vascular damage contributes to synaptic dysfunction and how it synergizes with amyloid pathology to cause neuroinflammation and cognitive decline remain poorly understood. Here, we show that the blood protein fibrinogen induces spine elimination and promotes cognitive deficits mediated by CD11b-CD18 microglia activation. 3D molecular labeling in cleared mouse and human AD brains combined with repetitive in vivo two-photon imaging showed focal fibrinogen deposits associated with loss of dendritic spines independent of amyloid plaques. Fibrinogen-induced spine elimination was prevented by inhibiting reactive oxygen species (ROS) generation or genetic ablation of CD11b. Genetic elimination of the fibrinogen binding motif to CD11b reduced neuroinflammation, synaptic deficits, and cognitive decline in the 5XFAD mouse model of AD. Thus, fibrinogen-induced spine elimination and cognitive decline via CD11b link cerebrovascular damage with immune-mediated neurodegeneration and may have important implications in AD and related conditions.